rifampin and 6-beta-hydroxycortisol

Endogenous metabolites of cytochrome P450 (CYP3A) are useful in predicting drug-drug interactions between in vivo CYP3A inhibitors and inducers for clinical applications of CYP3A substrate drugs. This study aimed to develop predictable markers of the magnitude of hepatic CYP3A induction and inhibition in healthy female subjects using pharmacometabolomics. Twelve female subjects received midazolam during three study phases: 1 mg midazolam (control phase), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). Throughout the study, blood samples were collected 24 h after midazolam administration and urine samples at 12-h intervals during the 24 h before and after midazolam administration for the analysis of endogenous steroid metabolites. A statistical model was generated to predict midazolam clearance using measurements of endogenous metabolites associated with the inhibition and induction of CYP3A. Mean midazolam clearance decreased to ∼20% of control levels during the inhibition phase and increased more than 2-fold during the induction phase. Of the urine and plasma metabolites measured, the 6β-hydroxycortisol/cortisol ratio was most significantly correlated with midazolam clearance during hepatic CYP3A inhibition and induction. Our results suggest that the urinary 6β-hydroxycortisol/cortisol ratio is the best predictor of hepatic CYP3A activity under both maximal inhibition and maximal induction. Furthermore, the predictive model including 6β-hydroxycortisol/cortisol as a covariate could be applied to predict the magnitude of CYP3A-mediated drug interactions.

Topics: Administration, Intravenous; Administration, Oral; Adult; Biomarkers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Enzyme Induction; Female; Humans; Hydrocortisone; Ketoconazole; Liver; Metabolic Clearance Rate; Metabolomics; Midazolam; Middle Aged; Rifampin; Young Adult

When developing new drugs appropriate markers for detecting induction and inhibition of cytochrome P450 3A enzymes (CYP3A) are needed. The aim of the present study was to evaluate the quinine/3-hydroxyquinine metabolic ratio (quinine MR) with other suggested markers for CYP3A induction: endogenously formed 4β-hydroxycholesterol, midazolam clearance in plasma and the 6β-hydroxycortisol/cortisol ratio in urine. We have previously performed a clinical trial in which 24 healthy subjects were randomized to take 10, 20 or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A induction. In newly analyzed data from this study we can show that the quinine MR could detect CYP3A-induction even at the lowest dose of rifampicin (10 mg) (p < 0.01), comparable to a 4β-hydroxycholesterol/cholesterol ratio and midazolam clearance. The median fold-induction for the quinine MR compared to baseline was 1.7, 1.8 and 2.6 for the three dosing groups (10, 20 and 100 mg). In conclusion, in this study the quinine MR was comparable to midazolam clearance as a measure of CYP3A activity but easier to determine since only a single blood sample needs to be drawn.

Topics: Biomarkers; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Hydrocortisone; Hydroxycholesterols; Midazolam; Quinidine; Quinine; Rifampin

Midostaurin, a multitargeted tyrosine kinase inhibitor, is primarily metabolized by CYP3A4. This midostaurin drug-drug interaction study assessed the dynamic response and clinical usefulness of urinary 6β-hydroxycortisol to cortisol ratio (6βCR) and plasma 4β-hydroxycholesterol (4βHC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.. Forty healthy adults were randomized into groups for either placebo or treatment with rifampicin 600 mg QD for 14 days. All participants received midostaurin 50 mg on day 9. Midostaurin plasma pharmacokinetic parameters were assessed. Urinary 6βCR and plasma 4βHC levels were measured on days 1, 9, 11, and 15.. Both markers remained stable over time in the control group and increased significantly in the rifampicin group. In the rifampicin group, the median increases (vs day 1) on days 9, 11, and 15 were 4.1-, 5.2-, and 4.7-fold, respectively, for 6βCR and 3.4-, 4.1-, and 4.7-fold, respectively, for 4βHC. Inter- and intrasubject variabilities in the control group were 45.6 % and 30.5 %, respectively, for 6βCR, and 33.8 % and 7.5 %, respectively, for 4βHC. Baseline midostaurin area under the concentration-time curve (AUC) correlated with 4βHC levels (ρ = -0.72; P = .003), but not with 6βCR (ρ = 0.0925; P = .6981).. Both 6βCR and 4βHC levels showed a good dynamic response range upon strong CYP3A4 induction with rifampicin. Because of lower inter- and intrasubject variability, 4βHC appeared more reliable and better predictive of CYP3A4 activity compared with 6βCR. The data from our study further support the clinical utility of these biomarkers.

Topics: Adult; Biomarkers; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Female; Humans; Hydrocortisone; Hydroxycholesterols; Male; Middle Aged; Protein Kinase Inhibitors; Rifampin; Staurosporine; Young Adult

CYP3A4, considered the most important enzyme in drug metabolism, is often involved in drug-drug interactions. When developing new drugs, appropriate markers for detecting CYP3A4 induction are needed. Our study compared endogenously formed 4β-hydroxycholesterol with the midazolam clearance in plasma and the 6β-hydroxycortisol/cortisol ratio in urine as markers for CYP3A4 induction. To this end, we performed a clinical trial in which 24 healthy subjects were randomized to 10, 20, or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A4 induction. The CYP3A4 induction could be detected even at the lowest dose of rifampicin (10 mg) via the estimated midazolam clearance, the 4β-hydroxycholesterol ratio (both P < 0.01), and the 6β-hydroxycortisol ratio (P < 0.05). For the three dosing groups (10, 20, and 100 mg), the median fold induction from baseline was 2.0, 2.6, and 4.0 for the estimated midazolam clearance; 1.3, 1.6, and 2.5 for the 4β-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6β-hydroxycortisol/cortisol ratio. In conclusion, the 4β-hydroxycholesterol ratio is comparable to midazolam clearance as a marker of CYP3A4 induction, and each may be used to evaluate CYP3A4 induction in clinical trials evaluating drug-drug interactions for new drugs.

Topics: Adult; Biomarkers; Cholesterol; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Induction; Female; Humans; Hydrocortisone; Hydroxycholesterols; Male; Metabolic Clearance Rate; Midazolam; Rifampin

This study aimed to evaluate endogenous metabolic markers of hepatic cytochrome P450 (CYP)3A activity in healthy subjects using a metabolomics approach. Twenty-four subjects received the following medication during the following three study periods: 1 mg of i.v. midazolam alone (control phase), 1 mg of i.v. midazolam after 4 days of pretreatment with 400 mg of ketoconazole once daily (CYP3A-inhibited phase), and 2.5 mg of i.v. midazolam after 10 days of pretreatment with 600 mg of rifampicin once daily (CYP3A-induced phase). During each study period, 24 h before and after the administration of midazolam, urine samples were collected at 12-h intervals for metabolomic analyses. We derived an equation to predict midazolam clearance (CL) based on several of these markers. We demonstrated that a combination of the concentrations and ratios of several endogenous metabolites and the CYP3A5*3 genotype is a reliable predictive marker of hepatic CYP3A activity as assessed by i.v. administration of midazolam.

Topics: Adult; Biomarkers; Cortisone; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Enzyme Induction; Gas Chromatography-Mass Spectrometry; Humans; Hydrocortisone; Hydroxycholesterols; Ketoconazole; Liver; Male; Metabolomics; Midazolam; Pharmacogenetics; Rifampin; Young Adult

Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6β-hydroxycortisol/ cortisol ratio, from a preinduction baseline of 5.8 ± 2.7 to 18.0 ± 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8-fold, and the maximum serum concentration (C(max)) and area under the serum concentration-time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the C(max) and AUC of nilotinib by 1.8- and 3-fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible.

Topics: Adult; Area Under Curve; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Induction; Enzyme Inhibitors; Female; Humans; Hydrocortisone; Ketoconazole; Male; Pyrimidines; Rifampin; Young Adult

To investigate if rifampicin is both an inducer and an inhibitor of repaglinide metabolism, it was determined whether the timing of rifampicin co-administration influences the pharmacokinetics of repaglinide.. Male volunteers ( n=12) participated in a randomised, two-period, crossover trial evaluating the effect of multiple doses of 600 mg rifampicin once daily for 7 days on repaglinide metabolism. Subjects were, after baseline measurements of repaglinide pharmacokinetics, randomised to receive, on either day 7 or day 8 of the rifampicin administration period, a single dose of 4 mg repaglinide and vice versa in the following period.. When repaglinide was given, together with the last rifampicin dose, on day 7, an almost 50% reduction of the median repaglinide area under the plasma concentration-time curve (AUC) was observed. Neither the peak plasma concentration (C(max)), time to reach C(max) (t(max)) nor terminal half-life (t(1/2)) was statistically significantly affected. When repaglinide was given on day 8, 24 h after the last rifampicin dose, an almost 80% reduction of the median repaglinide AUC was observed. The median C(max) was now statistically significantly reduced from 35 ng/ml to 7.5 ng/ml. Neither t(max) nor t(1/2) was significantly affected.. When rifampicin and repaglinide are administered concomitantly, rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. After discontinuing rifampicin administration, while the inductive effect on CYP3A4 and probably also CYP2C8 is still present, an even more marked reduction in the plasma concentration of repaglinide was observed. Our results suggest that concomitant administration of rifampicin and repaglinide may cause a clinically relevant decrease in the glucose-lowering effect of repaglinide, in particular when rifampicin treatment is discontinued or if the drugs are not administered simultaneously or within a few hours of each other.

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Carbamates; Chromatography, High Pressure Liquid; Cross-Over Studies; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Induction; Humans; Hydrocortisone; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Quinidine; Rifampin; Time Factors

To assess the influence of the CYP3A4 enzyme inducer rifampin on the pharmacokinetics of the immunosuppressant everolimus to provide guidance for their coadministration.. In this open-label, single-sequence, crossover study, 12 healthy subjects received a single oral 4-mg dose of everolimus alone and again after an 8-day pretreatment with rifampin 600 mg/d. Urinary excretion of 6beta-hydroxycortisol was measured at various time points during rifampin treatment as a marker of CYP3A4 induction.. Urine excretion of 6beta-hydroxycortisol was significantly elevated during treatment with rifampin compared with prestudy, indicating enzyme induction. When everolimus was coadministered during rifampin treatment, the apparent clearance of everolimus was significantly increased, on average by 172%. This was manifested as a decrease in maximum concentration in all subjects, on average by 58% (range 14-73%). The AUC remained unaffected in 1 subject (although 6beta-hydroxycortisol indicated enzyme induction) and decreased in the other 11 subjects. The average decrease in AUC in the full study population was 63% (range 0-82%). Everolimus half-life was reduced significantly, from an average of 32 hours to 24 hours.. In everolimus-treated patients for whom rifampin is indicated, alternative agents with less enzyme induction potential than rifampin could be considered. Alternatively, the dose of everolimus could be individually titrated based on everolimus therapeutic drug monitoring during rifampin therapy.

Topics: Adult; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Induction; Everolimus; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Middle Aged; Rifampin; Sirolimus

CYP3A is responsible for the metabolism of numerous endogenous and exogenous compounds. Several substrates of CYP3A have been investigated to assess the CYP3A-metabolizing capacity of an individual in an attempt to predict the rate of metabolism of other CYP3A substrates. Two such tests of CYP3A activity are the midazolam plasma clearance after its intravenous administration and the 6beta-OH cortisol urinary ratio. Possible correlations between these 2 tests were investigated before and after treatment with rifampin in a group of healthy volunteers.. Pharmacokinetic parameters of midazolam and 6beta-OH cortisol urinary ratio were evaluated in 8 volunteers before and after 6 days treatment with rifampin, a potent inducer of CYP3A, and after cessation of rifampin treatment.. Midazolam systemic clearance and the 6beta-OH cortisol urinary ratio were significantly higher at Days 7 and 10 than at Day 0. There was a strong positive correlation between these 2 parameters (r = 0.70, p < 0.001). In contrast, no correlation was observed between the ratio of the AUCs of 1'-OH midazolam vs. midazolam (AUC0-1(1'-OH)/AUC0-t(MDZ)) or the ratio of plasma concentration of 1'-OH midazolam vs. midazolam (C30 min(1'-OH)/C30 min(MDZ)) and the 6beta-OH cortisol urinary ratio (r = 0.05, p = 0.82; r = 0.04, p = 0.88, respectively). Considering only data obtained before or after treatment with rifampin, however, no correlation was observed between midazolam systemic clearance and the 6beta-OH cortisol urinary ratio.. These data demonstrate that there is a strong positive correlation between systemic midazolam clearance and 6beta-OH cortisol urinary ratio before and after induction. This suggests that the 6beta-OH cortisol urinary ratio test is a non-invasive alternative to the use of systemic midazolam clearance for monitoring the time-course of CYP3A induction.

Topics: Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Biomarkers; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Enzyme Induction; Enzyme Inhibitors; Female; GABA Modulators; Humans; Hydrocortisone; Male; Midazolam; Middle Aged; Oxidoreductases, N-Demethylating; Predictive Value of Tests; Rifampin

To evaluate the usefulness of 6 beta-hydroxycortisol as a screen for CYP3A induction in early-phase drug development.. Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 40 mg SB 216469 twice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day. All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24-hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6 beta-hydroxycortisol and 17-hydroxycorticosteroid concentrations.. Subjects in the rifampin group had a significant increase from predose value in the 24-hour urinary excretion of 6 beta-hydroxycortisol and the ratio of 6 beta-hydroxycortisol to 17-hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6 beta-hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio. The placebo and three active treatment groups did not show significant changes in either parameter.. Urinary excretion of 6 beta-hydroxycortisol may be useful as a screening tool in early-phase development to assess the potential for an investigational drug to induce CYP3A.

Topics: 17-Hydroxycorticosteroids; Adrenergic alpha-Antagonists; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Aryl Hydrocarbon Hydroxylases; Chromones; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Enzyme Induction; Humans; Hydrocortisone; Male; Oxidoreductases, N-Demethylating; Reference Values; Rifampin

To study the effect of rifampin (INN, rifampicin), a potent inducer of cytochrome P450, on the steady-state pharmacokinetics of delavirdine.. Twelve patients who were positive for human immunodeficiency virus, with CD4 counts ranging from 110 to 483/mm3, were randomized to two groups and studied in parallel. Both the control group (n = 5) and the rifampin group (n = 7) received 400 mg delavirdine mesylate every 8 hours for 30 days; subjects in the rifampin group took a 600 mg once-daily dose of rifampin on days 16 through 30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavirdine and its N-desalkyl metabolite concentrations with a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifampin by HPLC.. Delavirdine mesylate alone and in combination with rifampin was well tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (p < 0.049). In the rifampin group, delavirdine oral clearance increased by about 27-fold (p = 0.022), resulting in virtually negligible (< 0.09 mumol/L) steady-state through drug concentrations in all patients after 2 weeks of concurrent dosing of delavirdine mesylate and rifampin. The ratio of metabolite formation to elimination clearance for desalkyldelavirdine was significantly higher (3.9 +/- 1.2 versus 0.23 +/- 0.10) and delavirdine elimination half-life was significantly shorter (1.7 +/- 1.4 versus 4.3 +/- 1.3 hours) when delavirdine mesylate was taken with rifampin. Rifampin pharmacokinetic parameters on days 16 and 30 were similar to those previously reported for normal volunteers.. The findings of this study indicate that rifampin induces the metabolism of delavirdine. Therefore therapy with rifampin is contraindicated in patients receiving delavirdine mesylate.

Topics: Adult; Alkylation; Anti-HIV Agents; Antibiotics, Antitubercular; Aryl Hydrocarbon Hydroxylases; Blotting, Western; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Delavirdine; Dose-Response Relationship, Drug; Drug Interactions; Female; HIV Seropositivity; Humans; Hydrocortisone; Indoles; Liver; Male; Middle Aged; Oxidoreductases, N-Demethylating; Piperazines; Reverse Transcriptase Inhibitors; Rifampin

The effects of rifampin on the pharmacokinetics of fluconazole were analyzed in an open-label, placebo-controlled, parallel study. Sixteen healthy male volunteers, randomized into two groups, received 200 mg of oral fluconazole on days 1 and 22. On days 8 through 27, group I received oral rifampin, 600 mg/d, and group II received placebo. Fluconazole in serum was analyzed by HPLC. On days 1 and 22, respectively, the AUC (micrograms.hr/mL) (mean +/- SD) was 160.5 +/- 19.5 and 124 +/- 22.2 in group I, 152 +/- 25 and 152.8 +/- 33.9 in group II; the Kel (hr-1) was .0211 +/- .0030 and .0264 +/- .0040 in group I, .0219 +/- .0036 and .0216 +/- .0053 in group II. Cmax and Tmax did not change significantly in either group. Urinary 6 beta-hydroxycortisol/cortisol increased from 3.47 +/- 1.04 to 15.2 +/- 5.07 in group I, but was unchanged (3.54 +/- 1.33-4.26 +/- 2.36) in group II on days 1 and 22, respectively. The findings in this study indicate that rifampin induces the metabolism of fluconazole.

Topics: Administration, Oral; Adolescent; Adult; Drug Administration Schedule; Fluconazole; Humans; Hydrocortisone; Male; Middle Aged; Rifampin

CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4β-hydroxycholesterol (4β-OHC) and urinary 6β-hydroxycortisol-to-cortisol ratios (6β-OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (RIF; 20 mg/kg). In the present study, the CYP3A induction by RIF over a range doses of 0.2, 2 and 20 mg/kg (n = 4) was examined using CYP3A probe drugs (midazolam, triazolam and alprazolam) and the plasma and urinary endogenous CYP3A markers (4β-OHC and 6β-OHC/C). The sensitivity and relationship for detecting CYP3A induction was compared among the markers. Four days repeated oral administration of rifampicin to cynomolgus monkeys reduced the area under the plasma concentration-time curve of all CYP3A probe drugs in a rifampicin dose-dependent manner. Although the endogenous CYP3A markers (4β-OHC and 6β-OHC/C) were also changed for the middle (2 mg/kg) and high (20 mg/kg) doses of rifampicin, the fold-changes were relatively small, and CYP3A induction could not be detected at the lowest dose of rifampicin (0.2 mg/kg). In conclusion, CYP3A probe drugs are more sensitive for detecting CYP3A induction than endogenous CYP3A markers in cynomolgus monkeys, even for a short experimental period.

Topics: Alprazolam; Animals; Area Under Curve; Biomarkers; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Dose-Response Relationship, Drug; Drug Interactions; Hydrocortisone; Hydroxycholesterols; Macaca fascicularis; Male; Midazolam; Rifampin; Triazolam

The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose.. Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied. The hepatic CYP3A biomarkers 4β-hydroxycholesterol (4β-HC) and 6β-hydroxycortisol/cortisol ratio (6β-OHC/C) were monitored in in vivo studies. The static mechanistic model was used to quantitatively understand the in vitro-in vivo extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction-based drug-drug interactions (DDI).. All in vitro and in vivo data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto-induction and DDI liability in humans at the predicted efficacious dose.. The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study.

Topics: Administration, Oral; Animals; Computer Simulation; Cytochrome P-450 CYP3A; Drug Discovery; Drug Interactions; Enzyme Induction; Humans; Hydrocortisone; Hydroxycholesterols; Liver; Macaca fascicularis; Midazolam; Models, Biological; Pharmacokinetics; Rifampin; RNA, Messenger

To compare plasma 4β-hydroxycholesterol : cholesterol with urinary 6β-hydroxycortisol : cortisol as markers of cytochrome P4503A4 activity before and after treatment with rifampicin for 2 weeks.. 6β-hydroxycortisol and cortisol were determined by liquid chromatography tandem mass spectrometry and 4β-hydroxycholesterol was determined by gas chromatography-mass spectrometry in three groups of healthy volunteers.. Induction ratios for 6β-hydroxycortisol : cortisol were 1.8, 3.9 and 4.5 for 20 mg day(-1) , 100 mg day(-1) or 500 mg day(-1) of rifampicin, respectively. The corresponding ratios for 4β-hydroxycholesterol : cholesterol were 1.5, 2.4 and 3.8.. Plasma 4β-hydroxycholesterol : cholesterol gave similar induction ratios to urinary 6β-hydroxycortisol : cortisol.

Topics: Antibiotics, Antitubercular; Biomarkers; Cholesterol; Chromatography, Liquid; Cytochrome P-450 CYP3A; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydrocortisone; Hydroxycholesterols; Male; Rifampin

The aim of this study was to evaluate the effect of rifampicin co-administration on the pharmacokinetics of ruboxistaurin and its active metabolite, N-desmethyl ruboxistaurin and, in addition, to compare the changes in pharmacokinetics of ruboxistaurin and N-desmethyl ruboxistaurin with the urinary 6beta-hydroxycortisol : cortisol ratio. Ruboxistaurin is a specific protein-kinase-C beta inhibitor in clinical development for the treatment of diabetic microvascular complications.. This was a two-period, one-sequence study. Sixteen healthy male subjects completed both study periods. In period one, a single 64 mg oral dose of ruboxistaurin was administered. In period two, 600 mg rifampicin was administered daily for 9 days, during which another single 64 mg ruboxistaurin dose was administered on day 7. Blood samples were collected and assayed for ruboxistaurin and N-desmethyl ruboxistaurin. CYP3A4 induction was assessed by ratios of urinary 6beta-hydroxycortisol : cortisol (6beta-OHC : C) obtained via 24 h and morning-spot sampling techniques. Results Following repeated doses of rifampicin, both the mean C(max) and AUC(0,infinity) of ruboxistaurin were significantly reduced by approximately 95% (P < or = 0.001). For the metabolite, the mean C(max) decreased by 68% (P < or = 0.001), and AUC(0,infinity) decreased by 77% (P < or = 0.001). The t(max) values did not appear affected. The 6beta-OHC : C ratios from both 24 h and morning spot methods increased significantly, consistent with CYP3A4 induction.. The effect of rifampicin co-administration on the exposure of ruboxistaurin is consistent with ruboxistaurin being a substrate of CYP3A4. Therefore, co-administration with known CYP3A4 inducing agents (rifampicin, carbamazepine, phenobarbital, etc.) may decrease the concentrations of ruboxistaurin and N-desmethyl-ruboxistaurin. In this study, 6beta OHC : C ratios substantially underestimated the impact of rifampicin on ruboxistaurin.

Topics: Adult; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Induction; Enzyme Inhibitors; Humans; Hydrocortisone; Indoles; Male; Maleimides; Protein Kinase C; Rifampin

To study the effects of rifampicin on the pharmacokinetics and pharmacodynamics of nilvadipine.. Five healthy adult volunteers received nilvadipine (4 mg) orally before and after a 6 day treatment with rifampicin. Blood and urine were collected and assayed for plasma nilvadipine and urinary 6beta-hydroxycortisol and cortisol.. The treatment with rifampicin reduced the mean (+/- s.d.) AUC of nilvadipine from 17.4 +/- 8.4 to 0.6 +/- 0.4 microg l-1 h (mean difference -16.8 microg l-1 h, 95% CI -9.4, 24.2 microg l-1 h). While the administration of nilvadipine alone elicited a significant (P < 0.05) hypotensive (mean difference for diastolic blood pressure -8 mmHg, 95% CI -4, -12 mmHg) and reflex tachycardia (mean difference 5 beats min-1, 95% CI 1, 9 beats min-1), the treatment with rifampicin abolished these responses. The urinary 6beta-hydroxycortisol/cortisol ratio showed a significant (P < 0.05) increase from 10.3 +/- 4.0 to 50.3 +/- 24.6 by rifampicin: mean difference 40.1, 95% CI 20.4, 59.8.. Because rifampicin may greatly decrease the oral bioavailability of nilvadipine, caution is needed when these two drugs are to be coadministered.

Topics: Administration, Oral; Adult; Antibiotics, Antitubercular; Blood Pressure; Calcium Channel Blockers; Drug Interactions; Female; Heart Rate; Humans; Hydrocortisone; Male; Nifedipine; Rifampin

Cytochrome P-450 3A (CYP 3A) enzymes, the prominent subfamily in the cytochrome system, are expressed in various extrahepatic tissues. Until now, their expression has been demonstrated in human polymorphic neutrophils (PMNs) but not in lymphocytes using immunohistochemistry and immunoblot analysis. Moreover, their potential modulation has not been determined yet. To study such an expression in different peripheral blood cell populations, rifampicin (600 mg/day during 6 days) was given to 8 healthy subjects. PMNs and lymphocytes were isolated by centrifugation of whole white blood cell fractions using Ficoll gradients before drug administration, immediately after, and 3 days after drug withdrawal. PMN and lymphocyte smears and homogenates were subjected to immunostaining and immunoblotting, respectively, with a mouse monoclonal antibody recognizing all CYP 3A proteins. These proteins were quantified by densitometric analysis. Before and after rifampicin administration, a positive cytoplasmic staining was observed in all PMNs and in about 50% of lymphocytes. CYP 3A expression in lymphocytes was further confirmed by positive immunoblots for lymphocyte homogenates. Neither in PMNs nor in lymphocytes, induction of CYP 3A protein expression was observed after rifampicin treatment despite overall induction of CYP 3A activity assessed by the urinary excretion of 6beta-hydroxycortisol. These results demonstrate that CYP 3A proteins are constitutively expressed not only in PMNs but also in lymphocytes. However, in both cell lineages CYP 3A protein expression was not induced by rifampicin.

Topics: Adult; Antibodies, Monoclonal; Aryl Hydrocarbon Hydroxylases; Blotting, Western; Cell Separation; Cells, Cultured; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Cytoplasm; Enzyme Induction; Female; Humans; Hydrocortisone; Immunohistochemistry; Lymphocytes; Male; Middle Aged; Molecular Weight; Neutrophils; Oxidoreductases, N-Demethylating; Rifampin; Time Factors

A single spot urine collection to measure the ratio of 6 beta-hydroxycortisol (6 beta-OHC) to free cortisol (C) has been proposed as a research tool for the assessment of CYP3A4 induction. However, intraindividual variability in 6 beta-OHC/C under basal conditions and conditions of induction has not been prospectively evaluated, and findings on the correlation between morning spot and 24-hour urinary ratios have been conflicting. In this study, the variability in morning spot and 24-hour urinary 6 beta-OHC/C ratios was assessed in 15 healthy adult male volunteers before, during, and after oral administration of rifampin 600 mg once daily for 14 days. In addition, the correlation between morning spot and 24-hour urinary ratios measured under baseline, maximum induction, and postinduction was determined. Intraindividual coefficients of variation (CVs) at baseline for the morning spot and 24-hour ratios were 54.3% and 57.1%, respectively, and were not changed significantly during induction. No significant differences were detected in the variability between the morning spot and 24-hour ratios at baseline, maximum induction, or postinduction. A good correlation (r = 0.61, p < 0.0001) was detected between the mean morning spot and 24-hour urinary ratios. Mean (+/- SEM) percent increases in the morning spot and 24-hour ratios at maximum induction relative to baseline were 320% +/- 73% and 137% +/- 30%, respectively (p = 0.019). All 15 subjects had an increase in the mean morning spot ratio at maximum induction relative to baseline, whereas 12 subjects showed an increase in the mean 24-hour ratio. The time course of changes in the mean morning spot urinary ratio in response to a 14-day course of rifampin was also similar to that reported previously in a study using 24-hour urine collections. These findings suggest that measurement of the morning spot urinary 6 beta-OHC/C ratio is an effective and efficient method for evaluating the potential of investigational agents to induce CYP3A4.

Topics: Adolescent; Adult; Basal Metabolism; Circadian Rhythm; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Enzyme Induction; Humans; Hydrocortisone; Male; Middle Aged; Mixed Function Oxygenases; Periodicity; Prospective Studies; Rifampin

An indirect enzyme-linked immunosorbent assay (ELISA) for the detection of anti-6 beta-hydroxycortisol (6 beta-OHC) antibody has been developed. After immunization of 6 beta-OHC protein conjugates in New Zealand White rabbits, specific polyclonal antibody to 6 beta-OHC was detected by ELISA in which the wells of microtiter plates were coated with 6 beta-OHC conjugated to protein. The rabbit anti-6 beta-OHC antibody titer was above 1:500,000 dilution. Cross-reactivity with other structurally related steroids such as cortisol hydrocortisone was less than 5%. The sensitivity of the polyclonal antibody was comparable to previous studies reported, and was within the accepted detection limit for 6 beta-OHC in man and in laboratory animals. The assay has a low detection limit of 1 ng/ml, an intraassay variation of 3.1% and an interassay variation of 5.2%. The application of the anti-6 beta-OHC-based-ELISA to detect urinary 6 beta-OHC was tested by measuring the concentration of 6 beta-OHC in man before and after enzyme induction by rifampicin treatment. The mean 24 h urine output of 6 beta-OHC in man subjects was 370 +/- 105 micrograms and 1350 +/- 201 micrograms before and after rifampicin administration, respectively. This polyclonal anti-6 beta-OHC antibody-based ELISA can be modified to detect mouse anti-6 beta-OHC IgG with equally good precision and specificity which should be useful in screening positive clones of a 6 beta-OHC IgG secreting mouse hybridoma currently being developed for detecting enzyme induction of CYP3A4 in man and laboratory animals.

Topics: Adult; Animals; Antibiotics, Antitubercular; Antibodies; Antigen-Antibody Reactions; Enzyme-Linked Immunosorbent Assay; Humans; Hydrocortisone; Male; Mice; Rabbits; Rifampin; Sensitivity and Specificity

Induction of hepatic cytochrome P-450-dependent oxidative metabolism is related to an almost identical increase (30%) in both the liver weight and portal blood flow in animals. In humans by contrast, an increased liver blood flow (44%) but no significant increase in liver volume has been reported.. Therefore, we studied prospectively the relationship between P-450 induction by rifampicin, hepatic volume and portal blood flow in 10 healthy volunteers.. After a pre-treatment phase (day 1 to 7) the 10 volunteers received 600 mg/day of rifampicin from day 7 to 12. The urinary 6-beta-hydroxycortisol output as a measure of oxidative metabolism (CYP3A4) and portal blood flow (pulsed Doppler ultrasound) were determined on days 1, 7, 11 and 13. Hepatic magnetic resonance volumetry was performed on days 1 and 13.. Urinary 6-beta-hydroxycortisol output increased in all volunteers (P = 0.0051) from a median of 2.15 micrograms/day/kg (1.8-3.3 micrograms/day/kg) on day 1 to 9.9 micrograms/day/kg (5.7-14 micrograms/day/kg) on day 13. In 9 of 10 volunteers induction by rifampicin was related to an increase (P = 0.0218) in liver volume from a median of 1570 cm3 (1390-1830 cm3) to a median of 1690 cm3 (1420-1860 cm3). The portal flow as assessed by colour Doppler ultrasound did not change significantly between day 1 (median 22 cm/s (15-35 cm/s)) and day 13 (median 19 cm/s (16-39 cm/s)).. A fourfold increase of urinary 6-beta-hydroxycortisol output after induction of cytochrome P-450 by rifampicin is associated with a significant but less than 10% increase in human liver volume. No increase of portal perfusion as assessed by Doppler ultrasound could be detected in this study.

Topics: Adult; Cytochrome P-450 Enzyme System; Enzyme Induction; Humans; Hydrocortisone; Liver; Liver Circulation; Magnetic Resonance Imaging; Male; Portal System; Prospective Studies; Rifampin; Statistics, Nonparametric; Ultrasonography, Doppler, Pulsed

Experimental and clinical studies have led to the hypothesis that the phosphodiester signal obtained by 31P magnetic resonance (MR) spectroscopy may be a specific marker for the hepatic induction of oxidative metabolism (P450 induction) by phenobarbitone or ethanol. Systematic studies in humans are lacking. Therefore, we studied 10 volunteers who received rifampin (600 mg/d) for 6 days, resulting in a documented induction of oxidative metabolism as measured by an increase in urinary 6-beta-hydroxycortisol output in all volunteers (P = .0004). 31P-MR spectroscopy and 1H-MR relaxometry were performed before and after hepatic P450 induction. As shown by 31P-MR spectroscopy, the median phosphomonoester concentration (PME) relative to nucleoside triphosphate (NTP) increased by 21% from 0.63 (range, 0.40-0.89) before induction to 0.76 (0.49-1.67) after induction (P = .0451). The median level of phosphodiesters (PDE) relative to NTP increased by 28% from 4.82 (3.41-6.67) before induction to 6.18 (4.63-11.63) after induction (P = .0091). An increase in the level of inorganic phosphates (Pi) relative to NTP was observed, but changes were not significant. As shown by 1H-MR relaxometry, a nonsignificant trend of the liver parenchyma to shorter relaxation times was observed after P-450 induction. In conclusion, both PME/NTP and PDE/NTP ratios (measured by in vivo 31P-MR spectroscopy) increased significantly after hepatic induction with rifampin. Further clinical studies with 31P-MR spectroscopy must take into account the potential effects of P450-inducing agents.

Topics: Adult; Antibiotics, Antitubercular; Cytochrome P-450 Enzyme System; Enzyme Induction; Humans; Hydrocortisone; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Phosphorus; Phosphorus Radioisotopes; Rifampin

Rifampin was shown to relieve pruritus in cholestatic liver diseases. There has been much speculation about the origin of pruritus, but it has not yet been comprehensively explained. The role of bile acids in producing pruritus is obscure and still under debate. Since rifampin both inhibits the uptake of bile acids into the hepatocyte and strongly induces mixed-function oxidases in the liver, the beneficial effects of this drug might be a consequence of altered bile acid metabolism.. We investigated the influence of rifampin on urinary bile acid excretion with special respect to glucuronide and sulphate conjugates in 14 healthy volunteers before and after administration of rifampin, 600 mg x 7 days, using each subject as his or her own control.. Bile acid glucuronide excretion increased from 0.55 to 1.19 mumol/24 h. This was in particular due to a significant increase of the urinary excretion of the 6 alpha-hydroxylated hyocholic and hyodeoxycholic acids, the relative amounts of which accounted for about two thirds of the urinary bile acid excretion. Excretion of sulphates, however, decreased from 1.40 to 0.86 mumol/24 h due to a significantly reduced excretion of lithocholic acid sulphate. No changes in the excretion rates of other primary and secondary bile acids and no changes in their conjugation patterns were observed.. The results provide evidence that rifampin induces 6 alpha-hydroxylation of bile acids. The products are subsequently glucuronidated at the 6 alpha-hydroxy group, thus stimulating renal excretion of potentially toxic bile acids.

Topics: Adult; Antibiotics, Antitubercular; Bile Acids and Salts; Cholic Acids; Deoxycholic Acid; Female; Gas Chromatography-Mass Spectrometry; Glucuronates; Humans; Hydrocortisone; Hydroxylation; Male; Mixed Function Oxygenases; Rifampin; Sulfates

Staphylococcus aureus infections have been successfully treated in animal models with the combination of fleroxacin and rifampin. We studied the influence of rifampin, a potent cytochrome P-450 inducer, on the pharmacokinetics and biotransformation of fleroxacin in 14 healthy young male volunteers. Subjects were given 400 mg of fleroxacin orally once a day for 3 days to reach steady state. After a wash-out period of 2 days, the same subjects received 600 mg of rifampin orally once daily for 7 days. On days 5 to 7 of rifampin treatment, 400 mg of fleroxacin was again administered once daily. Concentrations of fleroxacin as well as its two major urinary metabolites, N-demethyl- and N-oxide-fleroxacin, in plasma and urine were determined by reverse-phase high-performance liquid chromatography. The extent of hepatic enzyme induction by rifampin was confirmed by a significant increase of 6-beta-hydroxycortisol urinary output from 160.8 +/- 41.4 to 544.8 +/- 120.7 micrograms/4 h. There were no significant changes in the peak fleroxacin concentration in plasma (6.3 +/- 1.2 versus 6.2 +/- 1.9 mg/liter), time to maximum concentration of fleroxacin in plasma (1.1 +/- 0.9 versus 1.3 +/- 1.1 h), or renal clearance (58.3 +/- 16.4 versus 61.9 +/- 19.2 ml/min). The area under the curve AUC (71.4 +/- 15.8 versus 62.2 +/- 13.7 mg.h/liter) and the terminal half-life of fleroxacin (11.4 +/- 2.2 versus 9.2 +/- 1.1 h) decreased (P < 0.05), while the total plasma clearance increased from 97.7 +/- 21.6 to 112.3 +/- 25.8 ml/min (P < 0.01). Despite being statistically significant, this 15% increase in total plasma clearance does not appear to be clinically relevant. Metabolic clearance by N demethylation was increased ( 6.9 +/- 2.4 versus 12.5 +/- 3.2 ml/min; P < 0.01), whereas clearance by N oxidation did not change (5.8 +/- 1.1 versus 5.8 +/- 1.5 ml/min). Fleroxacin elimination was slightly increased (about 15%) through induction of metabolic clearance to N-demethyl-fleroxacin. Since fleroxacin levels remained above the MIC for 90% of the tested isolates of methicillin-susceptible S. aureus for at least 24 h, dose adjustment does not appear necessary, at least for short-term treatments.

Topics: Adult; Anti-Bacterial Agents; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Induction; Fleroxacin; Humans; Hydrocortisone; Liver; Male; Rifampin; Staphylococcal Infections

A previous study has demonstrated that the urinary level of 6 beta-hydroxycortisol is a marker of liver CYP3A content after induction by rifampicin. To put in evidence an eventual genetic polymorphism for this cytochrome, the frequency distribution of 6 beta-hydroxycortisol excretion was investigated in 102 healthy Caucasians before and after 6 days of oral rifampicin administration (600 mg daily). After rifampicin treatment, a wide interindividual distribution was observed but no clear bimodality. Moreover the mean 6 beta-hydroxycortisol level was higher in women (n = 38) than in men (n = 64). These observations do not favour the existence of a CYP3A genetic polymorphism based on 6 beta-hydroxycortisol excretion but evoke a sexual dimorphism. However, CYP3A is composed of at least four enzymes and as the enzyme(s) responsible for cortisol 6 beta-hydroxylation is (are) not perfectly known, it can not be excluded that a genetic polymorphism does exist for one enzyme of this family.

Topics: 17-Hydroxycorticosteroids; Administration, Oral; Adult; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Humans; Hydrocortisone; Male; Oxidoreductases, N-Demethylating; Polymorphism, Genetic; Rifampin

The pharmacokinetics of nitrazepam and temazepam were investigated in 16 healthy volunteers before and after seven days of the administration of rifampin 600 mg/d and/or probenecid 500 mg/d. In order to determine the endoplasmatic reticulum enzyme function, 6-beta-hydroxycortisol excretion and antipyrine pharmacokinetic parameters were evaluated. After the administration of rifampin, the total body clearance of antipyrine and nitrazepam increased by 87% and 83%, respectively. After the combined treatment with rifampin and probenecid, the elimination of the two drugs was also increased, even though to a lesser extent (33%, 31%). After the administration of probenecid only, the total clearances of antipyrine and nitrazepam were decreased by 22% and 25%, respectively. The urinary clearance of the antipyrine metabolites also decreased. In norantipyrine and 4-OH-antipyrine, this was due to a significant reduction of glucuronide fraction (211 +/- 32 to 159 +/- 26 mg, and 259 +/- 39 to 191 +/- 25 mg). The sulphate fraction of norantipyrine increased by 18% and that of 4-OH-antipyrine by 21%. Apart from a reduced excretion of the glucuronide fraction, the pharmacokinetics of temazepam were neither altered significantly by probenecid nor by rifampin. According to the outcome of this investigation, probenecid seems to bring about not merely an inhibition of phase II but also an inhibition of phase I metabolization.

Topics: 17-Hydroxycorticosteroids; Adult; Antipyrine; Endoplasmic Reticulum; Humans; Hydrocortisone; Nitrazepam; Probenecid; Rifampin; Temazepam; Time Factors

1. Urinary excretion of 6 beta-hydroxycortisol, hepatic microsomal cortisol 6 beta-hydroxylase and the specific content of several forms of cytochrome P450 were measured in 8 to 14 patients before and after treatment with rifampicin (600 mg orally per day for 4 days). 2. Rifampicin treatment produced an average five fold increase in daily excretion of urinary 6 beta-hydroxycortisol. 3. Cortisol 6 beta-hydroxylase activity increased from 15 +/- 6 pmol min-1 mg-1 in organ donors (considered as 'control subjects') to 87 +/- 31 pmol min-1 mg-1 in rifampicin treated patients. 4. Among three forms of human P450 (P450IA, IIC and IIIA), (1), (2), measured by Western blots, only P450IIIA was significantly induced by the antibiotic. 5. Only antibodies against P450IIIA selectively inhibited cortisol 6 beta-hydroxylase in human liver microsomes. 6. Cortisol 6 beta-hydroxylase was correlated with P450IIIA specific content. 7. The urinary level of 6 beta-hydroxycortisol correlated with liver microsomal cortisol 6 beta-hydroxylase and P450IIIA specific content. 8. We conclude that P450IIIA is predominantly responsible for cortisol 6 beta-hydroxylase activity in human liver microsomes and that urinary 6 beta-hydroxycortisol is a marker of the induction of this cytochrome P450.

Topics: Adult; Aged; Biomarkers; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Enzyme Induction; Female; Humans; Hydrocortisone; Immunoblotting; Isoenzymes; Liver; Male; Microsomes, Liver; Middle Aged; Mixed Function Oxygenases; Rifampin; Tissue Donors

The effect of enzyme induction by antipyrine, phenobarbitone and rifampicin on the time-course of urinary 6 beta-hydroxycortisol (6 beta-OHC) excretion was investigated in healthy volunteers. The drugs were given chronically for either seven or 14 days. Significant increases in 6 beta-OHC excretion were observed after 4 days administration of antipyrine (1.2 g), 13 days administration of phenobarbitone (100 mg), and only 2 days administration of rifampicin (0.6 or 1.2 g). During 14 days rifampicin administration (1.2 g) 6 beta-OHC excretion, for individual subjects, reached a maximum on Days 11-14 when excretion was significantly greater than on day 7. On stopping rifampicin, in a 7-day study, excretion decreased over the next six days, but still remained significantly elevated compared to the original control values. These studies show that measurement of urinary 6 beta-hydroxycortisol provides a simple non-invasive method with which to monitor the time-course of enzyme induction by drugs in man. However, the method cannot be used to predict clinically important drug interactions until the cytochrome P-450 enzyme responsible for cortisol 6 beta-hydroxylation has been fully characterized.

Topics: Adult; Antipyrine; Enzyme Induction; Female; Humans; Hydrocortisone; Kinetics; Liver; Male; Mixed Function Oxygenases; Phenobarbital; Rifampin; Time Factors

The comparative enzyme inducing effects of rifabutin and the chemically related drug rifampicin have been investigated in 8 normal subjects. Rifampicin 600 mg daily for 7 days caused considerable shortening of the antipyrine half-life and a marked increase in antipyrine clearance, associated with an increased rate of conversion to norantipyrine and, to a lesser extent, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine. The urinary excretion of 6-beta-hydroxycortisol was also markedly increased, while plasma GGT activity showed only a slight albeit statistically significant elevation. In the same subjects, rifabutin in the proposed therapeutic dosage (300 mg daily) for 7 days also enhanced the metabolic elimination of antipyrine, with preferential stimulation of the demethylation pathway, and increased the excretion of 6-beta-hydroxycortisol, but the magnitude of the effects was significantly less than after rifampicin. No significant change in plasma GGT was seen. The results indicate that, contrary to the findings in animals, rifabutin does have enzyme inducing properties in man, although at the dosages assessed they were considerably less than those of rifampicin.

Topics: Adult; Antipyrine; Enzyme Induction; Female; gamma-Glutamyltransferase; Half-Life; Humans; Hydrocortisone; Male; Metabolic Clearance Rate; Microsomes, Liver; Rifabutin; Rifampin; Rifamycins

Haem and bilirubin metabolism was studied in seven healthy volunteers during 4 weeks treatment with rifampicin 600 mg at night. The serum unconjugated bilirubin concentration increased 2-3 fold in the first 24 h of treatment (P less than 0.01) and subsequently fell to below pretreatment values (P less than 0.05) during the third and fourth weeks of rifampicin therapy. In each subject, the activity in leucocytes of delta-aminolaevulinic acid (ALA) synthase increased and that of protoporphyrinogen (proto) oxidase decreased during the first week of therapy. The mean ALA synthase activity was most markedly increased on day 4 being seven-fold its pretreatment value (P less than 0.01), and the mean proto oxidase activity most depressed on day 2 at 50% its pretreatment value (P less than 0.02). There was increased urinary excretion of porphobilinogen (PBG) during the first week of therapy and increased excretion of porphyrins and PBG during the third week of treatment. The increase in ALA synthase activity and haem precursor excretion can be explained by the combination of increased haem demand for haemoprotein induction and partial block in haem synthesis due to reduced proto oxidase activity.

Topics: Adult; Antipyrine; Bilirubin; gamma-Glutamyltransferase; Half-Life; Heme; Humans; Hydrocortisone; Kinetics; Male; Porphyrins; Rifampin

Treatment of tuberculosis with rifampicin in patients with pre-existing adrenal failure has been reported to induce adrenal crisis due to alteration of cortisol metabolism by induction of hepatic mixed liver oxygenase enzymes. To determine whether mineralocorticoid metabolism is altered by rifampicin treatment, we established the pharmacokinetics of immunoreactive aldosterone. The metabolic clearance rate (MCR) and plasma half-life of this material were measured before and after 6 days of rifampicin treatment (600 mg/day) in seven patients with Addison's disease due to tuberculosis. Antipyrine clearance and urinary 6-beta-hydroxycortisol excretion was determined to demonstrate induction of the cytochrome P450 dependent enzymes. Infusion of aldosterone at a constant rate of 0.17 mg/h over 4.5 h produced steady state concentrations after 2 h, with no difference before and after rifampicin treatment (mean +/- SD, 1649 +/- 144 vs 1586 +/- 80 pg/ml, respectively). The disappearance curve of IR-aldosterone from plasma was biexponential. No change could be observed in the plasma half-lives (alpha-phase 29 +/- 1.9 min vs 30 +/- 1.5 min, beta-phase 129 +/- 3.2 min vs 126 +/- 4.3 min), the MCR (1.47 +/- 0.1 l/h/kg vs 1.46 +/- 0.1 l/h/kg), and the volume of distribution (9.9 +/- 1.9 vs 10.2 +/- 0.3 l). The antipyrine half-life decreased significantly from 12.2 +/- 2.6 h to 7.6 +/- 0.9 h (P less than 0.05) with a rise in antipyrine clearance from 0.38 +/- 0.07 to 0.80 +/- 0.23 ml/min/kg (P less than 0.05) and no change in the volume of distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Addison Disease; Adult; Aldosterone; Antipyrine; Female; Humans; Hydrocortisone; Male; Middle Aged; Rifampin; Tuberculosis

The elimination of diazepam and antipyrine and the urinary excretion of their metabolites were investigated in 21 healthy volunteers before and after 7 days of administration of antipyrine, 1200 mg, and rifampin, 600 or 1200 mg. After administration of antipyrine and rifampin in two doses, antipyrine total body clearance increased by 53% and 60% or 98%, respectively. The clearance to metabolite showed a preferential induction of the norantipyrine pathway with different proportions after antipyrine and rifampin; rifampin, 1200 mg, also enhanced the 4-hydroxyantipyrine pathway further. After antipyrine, diazepam total body clearance was increased by 102%, affecting all metabolic pathways to a similar extent. After rifampin in both doses, diazepam total body clearance rose equally to 300% and desmethyl- and 3-hydroxydiazepam metabolic clearance to 400%. Therefore rifampin preferentially affects norantipyrine or desmethyl- and 3-hydroxydiazepam metabolic formation, suggesting induction of different (iso)zymes of cytochrome P-450.

Topics: 17-Hydroxycorticosteroids; Adult; Antipyrine; Diazepam; Endoplasmic Reticulum; Humans; Hydrocortisone; Kinetics; Male; Microsomes, Liver; Rifampin

In 6 healthy volunteers the pharmacokinetics of bisoprolol under steady-state conditions was investigated over three consecutive phases: over 7 days of 10 mg of bisoprolol once daily per os, 7 days of 10 mg of bisoprolol once daily plus 400 mg of cimetidine t.i.d. and 14 days of 10 mg of bisoprolol and 600 mg of rifampicin once daily with adequate intervals free of medication. After therapy with bisoprolol alone peak plasma levels (Cssmax) of the beta-blocker were 55.5 +/- 6.4 ng/ml (means +/- SEM), area under the plasma level-time curve (AUC tau) was 597 +/- 70 ng/ml.h, total body clearance (CL) 15.8 +/- 1.8 l/h and elimination half-lives (t1/2 beta) 10.1 +/- 1.2 h. Cimetidine did not cause any significant changes in the pharmacokinetics of bisoprolol. Co-administration of rifampicin resulted in a decrease in Cssmax (43.0 +/- 6.9 ng/ml), AUC tau (397 +/- 54 ng/ml X h) and t1/2 beta (6.2 +/- 0.4 h). Accordingly, total body clearance increased to 23.8 +/- 2.5 l/h (p less than 0.05). In conclusion bisoprolol showed a statistically significant but probably clinically not important interaction with the enzyme-inducing drug rifampicin, but not with the enzyme inhibitor cimetidine.

Topics: Adrenergic beta-Antagonists; Adult; Bisoprolol; Cimetidine; Female; Half-Life; Humans; Hydrocortisone; Kinetics; Male; Microsomes, Liver; Propanolamines; Rifampin

To determine the effect of rifampicin therapy on hepatic oxidase activity in animal protein deficient patients antipyrine and quinine t 1/2 and 6B-hydroxycortisol (6B-OHF) excretion was studied in 8 Indian vegetarians during treatment for tuberculosis. In 4 patients at the start of treatment rifampicin/streptomycin caused a steady decline in by time antipyrine t 1/2 which was complete in 3 weeks, in one patient introduction of isoniazid produced a temporary reversal. After 4 months rifampicin/isoniazid 6B-OHF excretion was increased 2 to 10 fold in all patients although one followed serially showed a marked fall when isoniazid was begun. Decline in antipyrine t 1/2 persisted in 4 patients at the end of 18 months therapy and in one of these concurrent quinine t 1/2 confirmed partial isoniazid reversal of this decline. Rifampicin-mediated mixed function oxidase induction appeared similar to that reported for non-vegetarians and largely persists with combination therapy throughout treatment. Isoniazid can act as a competitive inhibitor of hepatic oxidase activity in some patients.

Topics: Antipyrine; Diet, Vegetarian; Drug Therapy, Combination; Enzyme Induction; Female; Half-Life; Humans; Hydrocortisone; India; Isoniazid; Liver; Male; Mixed Function Oxygenases; Quinine; Rifampin; Streptomycin; Tuberculosis

The effects of antipyrine (1200 mg day-1), phenobarbitone (100 mg day-1) and rifampicin (600 mg and 1200 mg day-1, respectively) administration for 7 days on sparteine metabolism and 6 beta-hydroxycortisol excretion were studied in panels of extensive (EM) and poor metaboliser (PM) subjects. Drug metabolism was induced in both EM and PM subjects by antipyrine and rifampicin pretreatment as indicated by increased excretion of 6 beta-hydroxycortisol. A 30% increase in metabolic clearance of sparteine was observed in EM subjects following rifampicin administration whereas in PM subjects no effect on the overall elimination of the drug was seen. The data indicate that the regulation of cytochrome P-450 isozyme involved in polymorphic debrisoquine/sparteine metabolism is predominantly under genetic control and that enzyme induction exerts only a marginal effect.

Topics: Adult; Antipyrine; Enzyme Induction; Female; Half-Life; Humans; Hydrocortisone; Male; Metabolic Clearance Rate; Middle Aged; Oxidation-Reduction; Phenobarbital; Rifampin; Sparteine

The effects of rifapentine (MDL 473) administration on hepatic mixed function oxidase activity in man have been investigated in six healthy volunteers. Administration of rifapentine (600 mg 48 h-1) for 10 days resulted in a significant reduction in antipyrine half-life (from 13.2 +/- 1.0 h to 7.7 +/- 0.4 h) and a corresponding increase in its total body clearance (from 41.8 +/- 5.5 ml min-1 to 67.4 +/- 5.6 ml min-1). Twelve days after stopping rifapentine administration, these values had largely returned to base-line. 24-Hour excretion of 6 beta-hydroxycortisol was significantly increased, by approximately three-fold, following administration of rifapentine for 10 days. Again, 12 days after stopping drug administration, 6 beta-hydroxycortisol excretion had returned to pretreatment values. Clearance of antipyrine to its three oxidative metabolites was increased by rifapentine administration, although the increase for 3-hydroxymethylantipyrine was not significant. The greatest increase (+140%) was observed for norantipyrine. Twelve days after the last dose of rifapentine, all values had returned to control levels. It is concluded that, like rifampicin, rifapentine is a potent inducer of mixed function oxidase activity in man and that the possibility of clinically significant drug interactions should be anticipated in the therapeutic use of this compound.

Topics: Adult; Antipyrine; Biotransformation; Enzyme Induction; Half-Life; Humans; Hydrocortisone; Male; Mixed Function Oxygenases; Rifampin; Saliva; Time Factors

The effect of rifampicin on the metabolism of isoniazid in human volunteer subjects has been investigated. The urinary metabolites of isoniazid after a single dose and after six daily doses of isoniazid plus rifampicin were examined. The isoniazid-rifampicin combination clearly increased the ratio of urinary 6-beta-hydroxycortisol to 17-hydroxycorticosteroids, indicating that induction of the microsomal enzymes had occurred. However, no significant changes in the urinary metabolites of isoniazid were detected, and therefore it is not possible to predict the effect of rifampicin on isoniazid hepatotoxicity.

Topics: 17-Hydroxycorticosteroids; Acetylation; Adult; Biotransformation; Creatinine; Humans; Hydrazines; Hydrocortisone; Isoniazid; Liver Function Tests; Male; Phenotype; Rifampin

The effect of 2 different drug combinations on liver microsomal activity was investigated in healthy volunteers by administering antipyrine 1200 mg and phenobarbitone 100 mg, or the same dose of antipyrine with rifampicin 600 mg daily for 14 days. The effect of rifampicin 1200 mg given for only 8 days was also studied. Before and after each drug regimen, estimates were made of the total body clearance of antipyrine, gamma-glutamyl-transferase (gamma-GT) and urinary excretion of 6-beta-hydroxycortisol as in vivo parameters of liver microsomal enzyme activity. Following combined antipyrine and phenobarbitone administration, the antipyrine clearance was increased by 80%, after antipyrine with rifampicin by 128%, and after rifampicin alone by 104%. 6-beta-hydroxycortisol, corrected for 17-hydroxycorticosteroids, increased from 2.6% to 8% following antipyrine plus phenobarbitone, from 4.4% to 27.9% following antipyrine plus rifampicin, and from 5.4% to 29.7% after rifampicin given alone. Based on previous studies, antipyrine given with phenobarbitone produced slightly more induction than phenobarbitone given alone. Following antipyrine 1200 mg with rifampicin 600 mg for 14 days a significantly greater increase in antipyrine clearance and 6-beta-hydroxycortisol excretion was observed than when either drug was given alone.

Topics: Adult; Antipyrine; Drug Combinations; Enzyme Induction; Female; Humans; Hydrocortisone; Male; Microsomes, Liver; Phenobarbital; Rifampin

In the present study two recently developed methods, a high performance liquid chromatography (HPLC) and a radioimmunoassay (RIA) for the estimation of 6 beta-hydroxycortisol in urine were compared. Both methods showed a very reliable intraassay variation of about 5.2 or 7.2% respectively. Using the baseline values of excretion during a 24-hour collecting period in human urine, and after induction of the liver microsomal enzyme system by different substances, both methods gave identical values. The HPLC-method still needs an extraction step at the beginning of the analytical procedure, while a direct measurement in the urine can be performed with the RIA. Furthermore, the RIA is not time consuming and is easy to perform. As the antiserum is highly specific there is no cross-reaction with other cortisol metabolites.

Topics: Antipyrine; Chromatography, High Pressure Liquid; Humans; Hydrocortisone; Phenobarbital; Radioimmunoassay; Rifampin

Topics: Adult; Anticonvulsants; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Enzyme Induction; Humans; Hydrocortisone; Male; Methods; Rifampin

Topics: Cross Reactions; Female; Humans; Hydrocortisone; Indomethacin; Radioimmunoassay; Rifampin