CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Nifedipine in Chinese Renal Transplant Patients

Abstract

Purpose: The drug-drug interactions (DDIs) of tacrolimus greatly contributed to pharmacokinetic variability. Nifedipine, frequently prescribed for hypertension, is a competitive CYP3A5 inhibitor which can inhibit tacrolimus metabolism. The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-nifedipine DDI in Chinese renal transplant patients.Method: All renal transplant patients were divided into CYP3A5*3/*3 homozygotes (group I) and CYP3A5*1 allele carriers (CYP3A5*1/*1 + CYP3A5*1/*3) (group II). Each group was subdivided into patients taking tacrolimus co-administered with nifedipine (CONF) and that administrated with tacrolimus alone (Controls). Tacrolimus trough concentrations (C0) were measured using high performance liquid chromatography. A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between CONF and Controls in group I and II, respectively. At the same time, a multivariate line regression analysis was made to evaluate the effect of variates on C0/D.Results: In this study, a significant DDI between tacrolimus and nifedipine with respect to the CYP3A5*3 polymorphism was confirmed. In group I (n = 43), the C0/D of CONF was significantly higher than in Controls [225.2 ± 66.3 vs. 155.1 ± 34.6 ng/ml/(mg/kg); p = 0.002]. However, this difference was not detected in group II (n = 27) (p = 0.216). The co-administrated nifedipine and CYP3A5*3/*3 homozygotes significantly increased tacrolimus concentrations in multivariate line regression analysis.Discussion: A CYP3A5 genotype-dependent DDI was found between tacrolimus and nifedipine. Therefore, personalized therapy accounting for CYP3A5 genotype detection as well as therapeutic drug monitoring are necessary for renal transplant patients when treating with tacrolimus and nifedipine.

In vitro and In silico studies of interactions of cathinone with human recombinant cytochrome P450 CYP(1A2), CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5

“…dihydropyridine calcium channel blockers (CCBs)) with anti-rejection medications (e.g. tacrolimus) are common [72] . CCBs can inhibit CYP3A5 and prevent tacrolimus metabolism [72] leading to toxicity in high levels whereas organ rejection if concentrations are too low.…”

Evaluation of Drug-Drug Interactions in Renal Transplant Patients

“…The mechanism of tacrolimus and nifedipine interaction seen in 34 prescriptions in our study is probably due to the nifedipine-induced inhibition of the hepatic metabolism of tacrolimus. Using tacrolimus together with nifedipine may increase the effects of tacrolimus (19)(20).…”

Population Pharmacokinetics of Tacrolimus in Pediatric Patients With Umbilical Cord Blood Transplant

“…Polymorphisms of CYP3A5 might be associated with interindividual variability of tacrolimus PK. [64][65][66] However, we did not include CYP3A5 genotypes as a covariate in the models. In the future, we will take this into consideration.…”