rifampin and Miosis

Alfentanil (ALF) is a validated probe for hepatic, first-pass, and intestinal cytochrome P450 (CYP) 3A activity, using plasma clearances, single-point concentrations, and noninvasive pupil diameter change (miosis). Assessing intravenous (i.v.) and oral drug disposition typically requires separate dosing. This investigation evaluated concurrent administration of oral deuterated and i.v. unlabeled ALF to assess both intestinal and hepatic CYP3A, and compare sequential and simultaneous dosing. ALF disposition was evaluated after strong hepatic and/or intestinal CYP3A induction and inhibition by rifampin, ketoconazole, and grapefruit juice. Using plasma ALF concentrations and area under the curve (AUC), clearance, or single-point concentrations, both simultaneous and sequential dosing provided equivalent results and detected hepatic and intestinal CYP3A induction and inhibition. Miosis better detected CYP3A modulation with sequential vs. simultaneous dosing. These results show that concurrent administration of oral deuterated and i.v. ALF, either sequentially or simultaneously, is an efficient and effective approach to assessing hepatic and intestinal CYP3A activity.

Topics: Administration, Oral; Adult; Alfentanil; Anesthetics, Intravenous; Area Under Curve; Beverages; Citrus paradisi; Cross-Over Studies; Cytochrome P-450 CYP3A; Deuterium; Drug Administration Schedule; Enzyme Induction; Enzyme Inhibitors; Female; Humans; Intestinal Mucosa; Ketoconazole; Liver; Male; Miosis; Rifampin; Young Adult

Levo-alpha-acetylmethadol (LAAM, levacetylmethadol) is a long-acting opioid agonist used for the prevention of opioid withdrawal. LAAM undergoes sequential N-demethylation to norLAAM and dinorLAAM, which are more potent and longer-acting than LAAM. Hepatic and intestinal microsomal N-demethylation in vitro is catalysed mainly by cytochrome P450 (CYP) 3A4; however, the role of CYP3A in LAAM disposition in humans in vivo is unknown. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) LAAM metabolism and bioactivation and, thus, clinical effects. It also related changes in LAAM disposition during enzyme inhibition or induction to any changes in pharmacological effect.. Healthy volunteers (n = 13) completed the three-way, randomised, balanced crossover study. Subjects received oral LAAM (0.25 mg/kg) after CYP3A induction (rifampicin [rifampin]), inhibition (troleandomycin) or nothing (controls). Plasma and urine LAAM, norLAAM and dinorLAAM were determined by electrospray high-performance liquid chromatography/mass spectrometry (HPLC/MS). Dark-adapted pupil diameter change from baseline (miosis) was the LAAM effect measure. Results were analysed by noncompartmental methods and by a combined pharmacokinetic/pharmacodynamic model.. Compared with controls, CYP3A induction (or inhibition) decreased (or increased) plasma LAAM concentrations and mean area under the plasma concentration-time curve from time zero to infinity (AUC(infinity) 199 +/- 91 [control] versus 11.3 +/- 4.0 [rifampicin] and 731 +/- 229 ng . h/mL [troleandomycin]; p < 0.05), and increased (or decreased) median formation clearances of norLAAM (1740 versus 14 100 and 302 mL/h/kg; p < 0.05) and dinorLAAM (636 versus 7840 and 173 mL/h/kg; p < 0.05). Surprisingly, however, CYP3A induction (or inhibition) decreased (or increased) mean plasma metabolite AUC from 0 to 96 hours (AUC(96)) [norLAAM + dinorLAAM] (859 +/- 241 versus 107 +/- 48 and 1185 +/- 179 ng . h/mL; p < 0.05) and clinical effects (mean miosis AUC(96) 128 +/- 40 versus 22.5 +/- 14.9 and 178 +/- 81 mm . h; p < 0.05). Clinical effects were best correlated with plasma norLAAM concentrations.. CYP3A mediates human LAAM N-demethylation and bioactivation to norLAAM and dinorLAAM in vivo. Paradoxically, however, CYP3A induction decreased and inhibition increased LAAM active metabolite concentrations and clinical effects. This suggests a CYP3A-mediated metabolic pathway leading to inactive metabolites, which predominates over CYP3A-dependent bioactivation. These results highlight the need for clinical investigations to validate in vitro drug metabolism studies.

Topics: Administration, Oral; Adult; Algorithms; Analgesics, Opioid; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Male; Methadyl Acetate; Miosis; Models, Biological; Receptors, Opioid, mu; Reproducibility of Results; Rifampin; Troleandomycin

The opioid alfentanil is a CYP3A4 substrate whose plasma clearance depends exclusively on hepatic CYP3A4 activity. Alfentanil clearance is an excellent in vivo probe for hepatic CYP3A4 activity and drug interactions in humans. However, such pharmacokinetic studies are invasive and time-consuming, and they require extensive analytical effort. This investigation tested the hypothesis that alfentanil-induced miosis (drug effect) can be used as a surrogate measure for alfentanil plasma concentrations and that alfentanil effect clearance will reflect plasma clearance; thus alfentanil can serve as a noninvasive probe for hepatic CYP3A4.. Six healthy volunteers were studied in a 3-way randomized crossover design. Each volunteer received 1 mg intravenous midazolam, followed 1 hour later by 15 microg/kg intravenous alfentanil, after CYP3A4 induction (rifampin [INN, rifampicin]), CYP3A4 inhibition (troleandomycin), and control. Dark-adapted pupil diameter and dynamic light response were measured coincident with venous blood sampling for up to 8 hours. Midazolam and alfentanil were quantified by gas chromatography-mass spectrometry. Plasma concentrations of alfentanil and midazolam (an additional CYP3A4 probe) and pupil diameter versus time data were analyzed by use of noncompartmental modeling. Pupil diameter change was analyzed analogously to determine the area under the alfentanil effect (miosis)-time curve (AUEC), effect clearance (CL(miosis)), and effect half-time.. Compared with control, CYP3A4 induction and inhibition significantly altered the clearances of alfentanil (2.8 +/- 1.4, 5.3 +/- 1.0, and 0.42 +/- 0.1 ml/kg/min, respectively; P <.05 versus control) and midazolam. Dark-adapted resting diameter (in millimeters) was the best measure of alfentanil pupil effects. Alfentanil-dependent miosis was significantly altered by CYP3A4 modulation, and log(diameter(0) - diameter(t)) versus time curves resembled alfentanil plasma disposition. AUEC(infinity) values after control, CYP3A4 induction, and inhibition were 280 +/- 150, 120 +/- 22, and 1030 +/- 240 mm x min, respectively (P <.05 versus control). Effect clearances (CL(miosis)) were 4.2 +/- 1.3, 8.8 +/- 2.4, and 1.2 +/- 0.8 microg/mm x min, respectively, and effect half-times were 62 +/- 23, 34 +/- 27, and 211 +/- 35 minutes, respectively (P <.05 versus control). CL(miosis) was significantly correlated with plasma clearances of alfentanil (r = 0.77, P <.001) and midazolam (r = 0.80; P <.001).. Alfentanil effect (miosis) may be a sensitive and reliable surrogate for plasma alfentanil concentrations. Alfentanil effect kinetics may be used as a noninvasive surrogate for conventional pharmacokinetics. CL(miosis) appears to be a suitable noninvasive in vivo probe for hepatic CYP3A4 activity, and it merits further investigation.

Topics: Adult; Alfentanil; Analgesics, Opioid; Antibiotics, Antitubercular; Area Under Curve; Cross-Over Studies; Female; GABA Modulators; Half-Life; Humans; Liver; Male; Midazolam; Miosis; Pilot Projects; Pupil; Rifampin

Systemic and oral clearances of alfentanil (ALF) are in vivo probes for hepatic and first-pass cytochrome P450 (CYP) 3A. Both ALF single-point plasma concentrations and miosis are surrogates for area under the concentration-time curve (AUC) and clearance and are minimal and noninvasive CYP3A probes. This investigation determined ALF sensitivity for detecting graded CYP3A induction and compared it with that of midazolam (MDZ). Twelve volunteers (sequential crossover) received 0, 5, 10, 25, or 75 mg oral rifampin for 5 days. MDZ and ALF were given intravenously and orally on sequential days. Dark-adapted pupil diameter was measured with blood sampling. Graded rifampin decreased plasma MDZ AUCs to 83, 76, 62, and 59% (intravenous (i.v.)) and 78, 66, 39, and 24% (oral) of control. Hepatic and first-pass CYP3A induction were detected comparably by plasma MDZ and ALF AUCs. Single ALF concentrations detected all CYP3A induction, whereas MDZ was less sensitive. ALF miosis detected induction of first-pass but not hepatic CYP3A.

Topics: Administration, Oral; Adolescent; Adult; Alfentanil; Analgesics, Opioid; Area Under Curve; Biological Availability; Cross-Over Studies; Cytochrome P-450 CYP3A; Enzyme Induction; Female; Half-Life; Humans; Hypnotics and Sedatives; Injections, Intravenous; Kinetics; Leprostatic Agents; Liver; Male; Midazolam; Miosis; Rifampin; Smoking; Young Adult