Effect of Multidrug Resistance-1 Gene Polymorphisms on Cyclosporine pharmacokinetics in Egyptian Renal Transplanted Patients

G Mostafa-Hedeab1, M Saber-Ayad2,3, IA Latif4, SO Elkashab5, S Abd elshafey6, TH Elshaboney7, MM Zaki8. 1Beni Suef faculty of medicine, Clinical pharmacology- 62111, Egypt, 2Faculty of medicine - cairo university, Pharmacology - 12613, Egypt, 3Sharjah College of Pharmacy, Pharmacology - 27272, United Arab Emirates, 4Faculty of medicine - cairo university, Biochemistry - 12613, Egypt, 5Faculty of medicine - cairo university, Internal medicne - 12613, Egypt, 6Beni Suef faculty of medicine, Clinical pathology - 62111, Egypt, 7Faculty of medicine - cairo university, Internal medicne - 12613, Egypt, 8Faculty of medicine - cairo university, Pharmacology - 12613, Egypt

Introduction: Cyclosporine A (CsA) is an important immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (P-gp), can influence the oral bioavailability and interpatient variability of CsA. We aimed at assessing the effect of MDR-1 gene polymorphisms at exon 26 (C3435T) and exon 11 (G1199A) on the CsA pharmacokinetics.

Materials & Methods: This study involved 40 (26 males (65%) and 14 females (35%) recent renal transplanted patients (age 27.5 range: 17-56 years). all patients included received CsA and were followed up for at least 3 months for CsA levels, before (C0) and 2 hours (C2) after administration of the CsA morning dose. CsA blood concentrations were determined by homogeneous enzyme immunoassay at 7th , 30th and 90th days after transplantation and genotyping for each polymorphism was identified using specific primers for restriction fragment length polymorphism (RFLP)-technique: They classified to responsive and non responsive group (according to their attacks of acute rejection (AR), their creatinine level and their need to shift to tacrolimus).

Results: - Out of 40 patients included, G/A polymorphism on exon 11 was the most frequent 77.5 % (31 pts), followed by patients with C3435T wild type 60% (24 pts) then mutant C3435T 40% (16 pts) and lastly wild type of G1199A 22.5% (9 pts). - Patients carrying mutant G/A polymorphism showed higher levels of cyclosporine A compared to wild type, at all measured levels of cyclosporine A - Patients with wild C/T polymorphism showed higher cyclosporine A trough level at day 7 than that of the mutant type. Discussions, Conclusion: Genotyping renal transplanted patients’ before transplantation may be helpful in choosing the best immunosuppressant and adjusting its dose. Patients carrying mutant G/A polymorphism should start with low dose CsA.

Bibliographic references:

Belitsky P, Dunn S, Jonhston A, et al. (2000): Impact of absorption profiling on efficacy and safety of cyclosporine therapy in transplant recipients. Clin Pharmacokinet.; 39: 117–125.

Mealey K. (2004): Therapeutic implications of the MDR-1 gene. Journal of Veterinary Pharmacology and Therapeutics 27:257–264.

Keywords: cyclosporine, polymorphisms, MDR gene, Renal transplant