Multi‐drug resistance gene‐1 (MDR‐1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by C0 or C2 measurements

Abstract

The intestinal efflux pump P-glycoprotein (P-gp), the product of the multi-drug resistance-1 (MDR-1) gene, significantly influences the pharmacokinetics of several drugs. Ciclosporin is a substrate for P-gp and is metabolized by cytochrome P450 (CYP) 3A enzymes. P-gp activity is affected by several known single nucleotide polymorphisms (SNPs) and haplotypes. MDR-1 genotypes of SNPs C1236T, G2677T/A and C3435T, as well as haplotypes C-G-C and T-T-T and CYP3A5*1 genotype (predictive of CYP3A5 expression), were related to ciclosporin blood concentrations measured at both 0 and 2 h after drug dosing in 197 stable renal transplant patients. Significant differences (of a magnitude unlikely to be relevant clinically) in dose-normalized blood ciclosporin concentrations were found only between MDR-1 genotypes of the C1236T SNP and between haplotype groups C-G-C and T-T-T in patients that were expressers of CYP3A5. MDR-1 SNPs and haplotypes and also CYP3A5*1 genotype, do not appear to have a major influence on ciclosporin pharmacokinetics.

Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients

“…This haplotype analysis was done to evaluate the in vivo effects of individual mutations because of the close linkage disequilibrium among the four ABCB1 SNPs. This was consistent with the recent results of Fredericks et al [26] who concluded that ABCB1 haplotypes have only a minor influence on CsA daily dose and dose-adjusted trough levels.…”

Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients: a meta-analysis

“…All included studies were published from 2003 to 2009, of which seven were performed on Asian patients [30][31][32][34][35][36][37][38], three on Caucasian patients [27][28][29], one on North Indian patients, and others did not present any information on ethnicity of the patients. In addition, all the publications were retrospective cohort studies and did not adopt blind design, thus affecting the quality of meta-analysis [26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Furthermore, different studies evaluated the effect of the CYP3A5*3 variant on CsA dose-adjusted C 0 in renal transplant patients at different time points posttransplantation.…”

“…Thirty-three publications were excluded for the following reasons: n = 26, inclusion criterion was unmet; n = 5, dates of the studies were not provided; and n = 2, duplicate citation or the same recipients were described in more than one publication. As a result, 14 clinical studies [26][27][28][29][30][31][32][33][34][35][36][37][38][39] with 1821 renal transplant recipients were included as summarized in Table 1 because they met our preset inclusion criteria of meta-analysis. All included studies were published from 2003 to 2009, of which seven were performed on Asian patients [30][31][32][34][35][36][37][38], three on Caucasian patients [27][28][29], one on North Indian patients, and others did not present any information on ethnicity of the patients.…”

“…To explore the causes that could affect the disposition of CsA, many clinical studies have been performed to evaluate the relationship between the CsA dose requirement, the dose-adjusted C 0 , and the loss-of-function CYP3A5*3 allele in renal transplant recipients. The clinical studies found that the results of these small-scale studies were not consistent [26][27][28][29][30][31][32][33][34][35][36][37][38][39]. The inconsistencies may be caused by the small number of patients and the use of different PK parameters (such as the dose-adjusted C 0 , the doseadjusted area under the plasma concentration-time curve, and the dose requirements used in different clinical studies) [31].…”

Emerging Role of Pharmacogenetic in Organ Transplantation

“…There are a number of conflicting reports regarding the CYP3A genotype influence on cyclosporine pharmacokinetic [27,28]. Therefore, a clear role of this polymorphism on cyclosporine metabolism has not been demonstrated.…”