tacrolimus and 6-beta-hydroxycortisol

To examine how the endogenous CYP3A4 phenotype and CYP3A5(*)3 genotype of Chinese renal transplant recipients influenced the dose-corrected trough concentration (C0/D) and weight-corrected daily dose (D/W) of tacrolimus.. A total of 101 medically stable kidney transplant recipients were enrolled, and their blood and urine samples were gathered. The endogenous CYP3A4 phenotype was assessed by the ratio of 6β-hydroxycortisol and 6β-hydroxycortisone to cortisol and cortisone in urine. CYP3A5(*)3 genotype was determined using PCR-RELP.. In overall renal transplant recipients, a multiple regression analysis including the endogenous CYP3A4 phenotype, CYP3A5(*)3 genotype and post-operative period accounted for 60.1% of the variability in C0/D ratio; a regression equation consisting of the endogenous CYP3A4 phenotype, post-operative period, body mass index, CYP3A5(*)3 genotype, gender, total bilirubin and age explained 61.0% of the variability in D/W ratio. In CYP3A5(*)3/(*)3 subjects, a combination of the endogenous CYP3A4 phenotype, post-operative period and age was responsible for 65.3% of the variability in C0/D ratio; a predictive equation including the endogenous CYP3A4 phenotype, post-operative period, body mass index, gender and age explained 61.2% of the variability in the D/W ratio. Base on desired target range of tacrolimus trough concentrations, individual daily dosage regimen was calculated, and all the observed daily doses were within the predicted range.. This study provides the equations to predict tacrolimus metabolism and dosage requirements based on the endogenous CYP3A4 phenotype, CYP3A5(*)3 genotype and other non-genetic variables.

Topics: Asian People; Cortisone; Cytochrome P-450 CYP3A; Humans; Hydrocortisone; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus

The oral plasma clearance of midazolam and the ratio of 6β-hydroxycortisol (6β-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6β-OHF/F in healthy Chinese.. Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6β-OHF concentrations were measured using UPLC.. There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6β-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6β-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus.. There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6β-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6β-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study.

Topics: Adult; Asian People; Biomarkers; Cross-Over Studies; Cytochrome P-450 CYP3A; Genotype; Humans; Hydrocortisone; Male; Midazolam; Polymorphism, Genetic; Tacrolimus; Young Adult

The combined clearance of endogenous 6β-hydroxycortisol and 6β-hydroxycortisone is suggested biomarker for in vivo cytochrome P450 3A (CYP3A) activity. We aimed to determine whether the combined clearance of these two markers together with information of biopharmaceutics classification system (BCS) of drugs could be used to predict CYP3A-mediated metabolism of immunosuppressants. The BCS of drug formulations were determined based on the solubility and permeability. Sixty-seven healthy subjects were divided into three groups and group 1 (n = 23), 2 (n = 22), and 3 (n = 22) received oral single dose of cyclosporine, tacrolimus, and sirolimus, respectively. Blood and urine samples were gathered at various times. The combined clearance of 6β-hydroxycortisol and 6β-hydroxycortisone correlated significantly with cyclosporine pharmacokinetics (p < 0.001) after oral dose of a BCS 1 formulation, whereas no relationships were seen after administration of tacrolimus and sirolimus formulations, both of which belonged to BCS 2. Regarding the biopharmaceutical characteristics, the endogenous CYP3A biomarker explains 74.5% of variability in oral cyclosporine clearance between individuals.

Topics: Biomarkers; Biopharmaceutics; Chemistry, Pharmaceutical; Cortisone; Cyclosporine; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Hydrocortisone; Immunosuppressive Agents; In Vitro Techniques; Liver; Male; Predictive Value of Tests; Sirolimus; Tacrolimus; Young Adult

The urinary ratio of 6beta-hydroxycortisol to cortisol (6beta-OHF/F) is considered to be the simplest and most practical method for estimation of hepatic cytochrome P450 3A4 (CYP3A4) activity as a non-invasive marker of human in vivo CYP3A4 activity. However, the inter- and intra-individual variability of the urinary 6beta-OHF/F ratio during liver regeneration and the effect of variability on optimal dose of tacrolimus have not yet been clarified. The objective of this study was to clarify the change in the urinary 6beta-OHF/F ratio during liver regeneration and to determine the effect of the liver graft function on the optimal tacrolimus dose in liver transplant recipients. Two liver transplant recipients (one male and one female) and eight healthy volunteers (five males and three females) were enrolled in this study. Urine samples were collected from the recipients from 08.00 hours for 24 h on post-transplant period, 1-10 and 21-30 days postoperatively. In the healthy volunteers, morning spot urine samples were collected at 08.00 hours. The mean urinary 6beta-OHF/F ratio in the immediate postoperative period was significantly low (p < 0.05). However, a marked difference in the regulation of CYP3A4 activity during liver regeneration was found in the two recipients. A significant correlation was found between the urinary 6beta-OHF/F ratio and the C/D ratio of tacrolimus (R = 0.658, p < 0.05). The urinary 6beta-OHF/F ratio is a useful probe for estimating the variability of CYP3A4 activity in liver transplant recipients in early postoperative phase. Future studies should evaluate the clinical usefulness of the urinary 6beta-OHF/F ratio as a predictor of tacrolimus pharmacokinetics in liver transplantation.

Topics: Adult; Biomarkers; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Infant; Liver; Liver Regeneration; Liver Transplantation; Male; Middle Aged; Tacrolimus

Many commonly used drugs are substrates for hepatic cytochrome P-450 3A in human beings, and its role in the metabolism of potentially toxic immunosuppressants has been highlighted (cyclosporine, FK 506). One hundred fifty human liver grafts were biopsied before and after liver transplantation, and levels of cytochromes P-450 3A, 1A2, 2D6 and 2C were estimated by means of the Western-blot technique and correlated with histological appearance, glycogen content and clinical course. In 15 of the grafts, cyclosporine oxidase was also measured, and in 12 of 15 recipients, urinary 6 beta-hydroxycortisol excretion was assayed. A wide range of cytochrome P-450 3A values were observed (25 to 366 arbitrary units/mg; mean, 105 +/- 63 arbitrary units/mg). In one graft (no. 730) no cytochrome P-450 3A was detectable on immunoblotting, despite increasing homogenate concentrations. In this sample, cytochromes P-450 1A2, 2D6, and 2C were present in normal ranges. Levels of cyclosporine oxidase and 6 beta-hydroxycortisol in the urine specimens of the recipient were found to be low. The recipient of graft 730 experienced reversible complications of FK 506 therapy despite adherence to the administration protocol and drug plasma level in the normal range. The subsequent appearance of the cytochrome P-450 3A was associated with the consequent tolerance of oral FK 506. The absence of detectable amounts of P-450 3A in one biopsy from a donated human liver graft dramatically emphasizes the extreme range of this enzyme levels and has important clinical implications.

Topics: Adolescent; Adult; Child; Cyclosporine; Cytochrome P-450 Enzyme System; Female; Humans; Hydrocortisone; Immunoblotting; Isoenzymes; Kidney; Liver; Liver Transplantation; Male; Middle Aged; Oxidoreductases; Tacrolimus