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Aim: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.Methods: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.Results: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.Conclusion: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.

The objective of this study was to evaluate the effect of the CYP3A5*3allele on the pharmacokinetics of tacrolimus and amlodipine, and drug-drug interactions between them in healthy subjects. Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a randomized, 3-period, 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype. A single-dose and multiple-dose study were designed. A 96-h pharmacokinetic study followed either tacrolimus or amlodipine dose, and the washout periods between the study phases were 14 days. In the single-dose study, apparent oral clearance (CL/F) of tacrolimus (5 mg) in CYP3A5 expressers was 3.8-fold (p = 0.008) higher than that in CYP3A5 non-expressers. Amlodipine decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold (p = 0.005), while it had no effect on that in CYP3A5 non-expressers. The CL/F of amlodipine in CYP3A5 non-expressers was 2.0-fold (p = 0.001) higher than that in CYP3A5 expressers. Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold (p = 0.016) while it had no effect on that in CYP3A5 non-expressers. Tacrolimus slightly reduced the AUC0−∞of amlodipine in both CYP3A5 expressers and non-expressers. Dose adjustment of tacrolimus should be considered according to CYP3A5*3 genetic polymorphism when tacrolimus is coadministered with amlodipine.

To determine whether functional polymorphisms of glutathione S-transferase type 1 (GSTM1) and aldehyde dehydrogenase-2 (ALDH2) affect the isosorbide 5-mononitrate (IS-5-MN) response, and the role of the calcitonin gene-related peptide (CGRP) in IS-5-MN response in healthy volunteers.