Logo Annals of Transplantation Logo Annals of Transplantation Logo Annals of Transplantation

26 September 2012

Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients

Dorota ŻochowskaABCDEF, Janusz WyzgałCDF, Leszek PączekADF

DOI: 10.12659/AOT.883456

Ann Transplant 2012; 17(3): 36-44

Abstract

Background: Calcineurin inhibitor (cyclosporine, CsA) and mTOR inhibitors (sirolimus, SRL) – immunosuppressants used to prevent allograft rejection after renal transplantation – have a narrow therapeutic index and show considerable inter-individual pharmacokinetic differences. Differences in expression and activity of cytochrome P450 (CYP) 3A4 and 3A5 affect these pharmacokinetics; cytochrome activity differences are associated with CYP genetic polymorphisms.
Material/Methods: This study evaluated the effects of polymorphisms in CYP3A4 and CYP3A5 on immunosuppressive drug-dose adjusted trough blood concentrations. One hundred renal transplant recipients were genotyped for CYP3A4*1B and CYP3A5*3 using PCR-RFLP. Blood concentrations of CsA and SRL were determined by EMIT and HPLC/UV, respectively.
Results: The allelic frequencies of CYP3A4*1B and CYP3A5*3 in the study group were 2.5% and 96.5%, respectively. The mean cyclosporine dose in CYP3A4*1/*1B subjects was 455.04±128.68 mg/day vs. 261.68±64.72 mg/day in CYP3A4*1/*1 subjects (p<0.001). The mean cyclosporine dose-adjusted trough blood concentrations (ng/ml per mg/kg body weight) in CYP3A4*1/*1B subjects were lower than in the CYP3A4*1/*1 group (37.06±10.38 vs. 44.63±13.99; p<0.218). The mean cyclosporine dose in CYP3A5*1/*3 subjects was 400.65±164.97 mg/day vs. 263.52±64.39 mg/day in CYP3A5*3/*3 subjects (p<0.022). No association was detected between sirolimus trough blood concentration (C0) or dose requirement, and CYP3A4 or CYP3A5 genotype.
Conclusions: Genetic polymorphisms in CYP3A4 and CYP3A5 may underlie inter-individual differences in cyclosporine pharmacokinetics after renal transplantation. Patients with at least 1 functional CYP3A5*1 or CYP3A4*1B allele require significantly higher doses of cyclosporine to reach target drug levels compared to patients with the CYP3A4*1 or CYP3A5*3 alleles.

Keywords: genetic polymorphism, Pharmacokinetics, immunosuppression, Cyclosporine, Sirolimus

0 Comments

In Press

20 Jan 2022 : Original article  

Impact on Waitlist Outcomes from Changes in the Medical Eligibility of Candidates for Simultaneous Liver-Ki...

Ann Transplant In Press; DOI: 10.12659/AOT.934850  

19 Jan 2022 : Original article  

Carbohydrate Metabolism Disorders in Relation to Cardiac Allograft Vasculopathy (CAV) Intensification in He...

Ann Transplant In Press; DOI: 10.12659/AOT.933420  

18 Jan 2022 : Original article  

PLGA+Fe₃O₄+PFP Nanoparticles Drug-Delivery Demonstrates Potential Anti-Tumor Effects on Tumor Cells

Ann Transplant In Press; DOI: 10.12659/AOT.933246  

17 Jan 2022 : Original article  

Impact of Thyroid Incidentaloma on Liver Transplant: A Study of 1010 Recipients at a Single Center

Ann Transplant In Press; DOI: 10.12659/AOT.934988  

Most Viewed Current Articles

29 Dec 2021 : Original article  

Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Sys...

DOI :10.12659/AOT.933588

Ann Transplant 2021; 26:e933588

22 Dec 2021 : Original article  

Comparison of Coronary Artery Calcium Scoring with Dobutamine Stress Echo for Detection of Coronary Artery ...

DOI :10.12659/AOT.934163

Ann Transplant 2021; 26:e934163

12 Jan 2022 : Original article  

Risk Factors for Developing BK Virus-Associated Nephropathy: A Single-Center Retrospective Cohort Study of ...

DOI :10.12659/AOT.934738

Ann Transplant 2022; 27:e934738

01 Dec 2021 : Original article  

Solid-Phase C1q/C3d Fixing Readouts Correlate with High Median Fluorescence Intensity (MFI) De Novo Donor-S...

DOI :10.12659/AOT.934175

Ann Transplant 2021; 26:e934175

Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358