Influence of MDR-1 CYP3A4 and CYP3A5 Genotypes/Haplotypes on Sirolimus Pharmacokinetics and Pharmacodynamics in Patients With Renal Transplantation

The immunosuppressant sirolimus is a substrate for the drug efflux pump p-glycoprotein

(Pgp) and the hepatic and intestinal drug metabolizing enzyme cytochrome P450 3A4/5

(CYP3A4/5). Single nucleotide polymorphisms (SNPs) in the multi-drug resistance (MDR)-1

gene which encodes for the Pgp, CYP3A4, and CYP3A5 genes have been shown to be associated with altered metabolism of various drugs including the immunosuppressants cyclosporine and tacrolimus. This protocol will evaluate the effects of MDR-1, CYP3A4, and CYP3A5 gentotypes/haplotypes on the pharmacokinetics and pharmacodynamics of sirolimus in patients with renal transplantation. All patients who had kidney transplantation at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Transplant Branch, participated in one of the NIDDK therapeutic protocols, and have received sirolimus will be enrolled in this study. Selected MDR-1, CYP3A4, and CYP3A5 SNPs will be determined by polymerase chain reaction based methods using existing patient blood samples. Demographic, pharmacokinetic, and pharmacodynamic data will be collected from the medical information system, NIDDK transplant database, and medical records of these patients. Population pharmacokinetic parameters and pharmacodynamic measurements will then be compared among patients with different MDR-1, CYP3A4, and CYP3A5 genotypes/haplotypes. Results from this study will help to understand the effects of pharmacogenetics on sirolimus pharmacokinetics and pharmacodynamics, and will provide information for rationalizing sirolimus dosing in patients with renal transplantation.