The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta‐Analysis

Abstract

Cyclosporine A (CsA) is a substrate of the multi-drug efflux pump P-glycoprotein (P-gp) encoded by ABCB1. Among the various single nucleotide polymorphisms (SNPs) of ABCB1, C3435T has been extensively investigated to determine the relationship with the pharmacokinetics of CsA. However, the results are controversial. This meta-analysis was designed to evaluate the influence of C3435T SNP on the dose-adjusted trough (C 0 /D) and peak (C max /D) concentrations of CsA. Based on a literature search of four authoritative databases, 13 studies since 2001 concerning 1293 kidney transplant recipients were included. The results indicated a significant difference of C 0 /D and C max /D between 3435CC and 3435TT genotype carriers (weighted mean difference (WMD) of C 0 /D: 4.18 (ng ml À1 )/(mg kg À1 ), 95% CIs: 1.00-7.37, p = 0.01; WMD of C max /D: 20.85 (ng ml À1)/ (mg kg À1 ), 95% CIs: 2.25-39.46, p = 0.03). Subgroup analysis by ethnicity demonstrated that C 0 /D was lower in Asian CC versus TT genotype carriers (WMD = 10.32 (ng ml À1)/(mg kg À1 ), 95% CIs: 4.78-15.85, p = 0.0003) but did not vary by genotype for Caucasian recipients. Moreover, significant variation of C 0 /D was found at 1 week and 1-3 months after transplantation between CC and TT genotype carriers. Therefore, this meta-analysis showed a correlation between ABCB1 C3435T polymorphism and the dose-adjusted concentration of CsA. Patients with 3435CC genotype will require a higher dose of CsA to achieve target therapeutic concentrations when compared with 3435TT carriers after kidney transplantation, especially in the Asian population and especially during the early and middle time periods after transplantation.Cyclosporine A (CsA), a calcineurin inhibitor, has been widely used for kidney transplant recipients to avoid allograft rejection [1]. However, CsA has a narrow therapeutic index and large interindividual pharmacokinetic variability [2,3]. To achieve the desired efficacy and limit side-effects, the individual trough or peak CsA concentration is routinely monitored [4]. Exploring the factors behind the large interindividual variability of CsA will help to develop a more reasonable individualized dosage regimen for kidney transplantation recipients. Genetic polymorphisms of drug metabolism enzymes and drug transporters have recently been considered as an important determinant of pharmacokinetic variation [5,6].CsA is a substrate of the multi-drug efflux pump P-glycoprotein (P-gp), which acts as an ATP-dependent transmembrane transporter and limits the bioavailability of drugs by decreasing their absorption from the intestinal lumen and enhancing their excretion [7]. P-gp is encoded by the multidrug resistance gene-1 (ABCB1). More than 50 single nucleotide polymorphisms (SNPs) in the corresponding gene sequence (ABCB1) of P-gp have been identified to date. In particular, exon 12 (C1236T), exon 21 (G2677T/A) and exon 26 (C3435T) were shown to play an important role in the expression and function of P-gp and have a functional impact on the pharma...

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

“…However, none of the changes in plasma concentrations seemed to be clinically relevant. Conversely, a recent meta-analysis of 1293 kidney transplant patients showed that C 0 /D values were significantly lower in Asian recipients with the 3435CC genotype but did not vary by genotype in Caucasians [96]. A recent study demonstrated a significant increase in intracellular concentrations among 3435TT carriers, though there were only slight changes in plasma concentrations [97].…”

Correlation between gene polymorphism and blood concentration of calcineurin inhibitors in renal transplant recipients

“…Multi-drug resistance gene (MDR1). Seven systematic reviews [16,17–22] stated the MDR1 genotype: 5 [16,18–21] were MDR1 C3435T and the remaining 2 [17,22] were MDR1 C1236T and MDR1 G2677T/A. All reviews investigated the effect of MDR1 polymorphisms on CNI C 0 /D.…”

“…All reviews investigated the effect of MDR1 polymorphisms on CNI C 0 /D. Of 5 reviews [16,18–21] with genotype MDR1 C3435T and CNI cyclosporin A or FK506, 2 reviews [18,19] of cyclosporin A showed that the C 0 /D of CC carriers was lower than that of TT carriers, 1 review [20] of FK506 showed that the C 0 /D of CC carriers was lower than that of TT carriers or CT carriers, and 2 reviews [16,21] of FK506 showed no significant difference between CC carriers and CT or TT carriers. In a review [17] of genotype MDR1 C1236T with cyclosporin A, there was no significant difference between CC carriers and CT or TT carriers.…”

Pharmacogenetics of Immunosuppressants in Solid Organ Transplantation: Time to Implement in the Clinic

“…Subgroup analysis by ethnicity demonstrated that in Asians, Cmin/D was lower in CC versus TT genotype carriers but did not vary for Caucasian recipients. This meta-analysis showed that patients with 3435CC genotype will require a higher dose of Cs to achieve target drug blood concentrations when compared with 3435TT carriers, especially in the Asian population and especially during the early and middle time periods after transplantation [43].…”