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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 AND METHODS 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.

SUBMITTER: Kotowski MJ

PROVIDER: S-EPMC6400024 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Kotowski Maciej J MJ Bogacz Anna A Bartkowiak-Wieczorek Joanna J Tejchman Karol K Dziewanowski Krzysztof K Ostrowski Marek M Czerny Bogusław B Grześkowiak Edmund E Machaliński Bogusław B Sieńko Jerzy J

Annals of transplantation 20190225

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 require ...[more]

PMID: 30799432

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Project description:Background and objectiveThe association between the CYP3A4*1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients.MethodsStudies evaluating the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1.ResultsSeven studies (involving 1182 adult renal transplant recipients) were included in this meta-analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4*1/*1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4*1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4*1/*1 European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C0/Dose ratio) was significantly higher in CYP3A4*1/*1 recipients than in CYP3A4*1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation.ConclusionBased on our meta-analysis, the CYP3A4*1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).

Dataset Information

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

Publications

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

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