GENETIC POLYMORPHISMS OF CYP3A5 AND MDR1 ON CYCLOSPORINE CONCENTRATION IN THE EARLY STAGE AFTER RENAL TRANSPLANTATION.

The immunosuppressive drug cyclosporine with a narrow therapeutic range and variable pharmacokinetic characteristics among individuals is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNPs) in these genes are associated with deficient protein expression and reduced in vivo activity. We postulated that, in renal transplant recipients, these SNPs could be associated with interindividual variations in cyclosporine pharmacokinetics.

Materials & Methods: CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis in 88 Iranian renal transplant patients receiving cyclosporine. Whole blood trough cyclosporine concentration was measured by radioactive immunosorbent assay and dose-adjusted concentration (ng/mL per mg/kg/d) was calculated at 1 to 3 days, 1 week, and 1 month after transplantation.

Results: The MDR-1 wild -type genotype (3435CC) was observed in 17 patients (19 %), whereas 45 (51%) patients were heterozygous (3435CT), and 26 (30%) patients were homozygous (3435 TT) for the mutation. In early days after transplantation, we found a correlation between the concentration/dose ratio and exon 26 MDR SNP (33.3±15.24 in the CT group vs. 44.1±28.4 [µg mg/L/kg] in the TT group, P=0.019). This ratio was significantly higher in subjects homozygous for the mutation (3435TT). This significant difference was not seen in 1 week and 1 month after transplantation. Accordingly, in this study all patients had CYP3A5*3/*3 genotype, so we could not find any differences among the CYP3A5*1/*3 genotypes.

Conclusion: MDR-1 (3435CC) polymorphisms are associated with cyclosporine pharmacokinetics and dose requirements in renal transplant recipients. Pharmacokinetic methods could be employed to help initial dose selection and to individualize immunosuppressive therapy. But it is important to say that one of the reasons that our population showed drug toxicity with lower dose of drug due to this genetic polymorphism at Cyp3A5 is that the drug couldn't be metabolized correctly and fast. So Iranian population need lower dose of cyclosporine