Effect of Multidrug-Resistant 1 (MDR1) and CYP3A4*1B Polymorphisms on Cyclosporine-Based Immunosuppressive Therapy in Renal Transplant Patients

Abstract

Background Immunosuppressive drugs such as cyclosporine A (CsA) are characterized by a narrow therapeutic range and high interindividual pharmacokinetic variations. Therefore, the effective monitoring of drug serum level is crucial for successful therapy. This variability can be caused by polymorphisms in genes encoding drug transporters and enzymes responsible for biotransformation. The aim of this study was to determine the relationship between CYP3A4*1B and MDR1 polymorphisms and dose requirements to achieve the target therapeutic range for CsA. Material/Method The study group consisted of 184 patients after kidney transplantation who were treated with immunosuppressive therapy. The MDR1 3435C>T and CYP3A4*1B polymorphisms were determined by the real-time PCR using the LightCycler ® 480 device (Roche Diagnostics). Results Patients with the CYP3A4*1/*1 genotype received the lowest mean dose of CsA compared to CYP3A4*1/*1B, and had a higher average drug concentration in the blood. In the case of MDR1 3435C>T polymorphism, we observed that patients with the CC genotype received lower doses of CsA than patients with the CT and TT genotypes. Average drug concentration in the blood was comparable to individuals with different MDR-1 genotypes. Analysis of dependence between both polymorphisms and concentration/dose ratio showed no statistically significant differences. Conclusions The characterization of CYP3A4*1B and 3435C>T MDR1 polymorphism cannot provide useful guidance for individualizing CsA dosages in renal transplant patients by indicating the optimal dose of these drugs without exposing patients to possible adverse effects associated mainly with nephrotoxicity.

CYP and SXR gene polymorphisms influence in opposite ways acute rejection rate in pediatric patients with renal transplant

“…The role of changes in drug metabolism, induced by polymorphisms of a number of genes, has been repeatedly underlined in the last two decades [11][12][13][14][15][16][17][18][19].…”

“…It is metabolized by cytochrome P-450, encoded by the CYP genes cluster. It is well known that polymorphisms of the intracellular metabolizer enzyme CYP and the trans-membrane transport protein ABCB1 may influence enzymatic intracellular activity, modifying drugs metabolism [11][12][13][14][15][16][17][18][19]. Patients with the A allele on CYP3A5*3 need to double the dose of tacrolimus in order to reach therapeutic blood concentration [20].…”

Pharmacokinetics and Toxicokinetics Roles of Membrane Transporters at Kidney Level

“…In addition, several ROS, like the superoxide radical, are involved in cyclosporineassociated nephrotoxicity (70). CsA is a substrate of P-gp, being excreted from renal proximal tubular cells by this protein (72).…”

The effect of CYP3A4 genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors in renal transplant recipients: a systematic review and meta-analysis protocol

“…Several primary studies have investigated the relation of CYP3A SNPs and pharmacokinetics of CNIs in solid organ transplant recipients, but the results are controversial [17-24]. Furthermore, few meta-analysis studies have appraised the effects of CYP3A4 SNPs on the pharmacokinetics of tacrolimus [25] and cyclosporine A [26, 27], which have not yielded conclusive results in renal transplant recipients.…”