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

Abstract

BackgroundImmunosuppressive 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/MethodThe 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).ResultsPatients 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.ConclusionsThe 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.