CYP3A5 Genotype Markedly Influences the Pharmacokinetics of Tacrolimus and Sirolimus in Kidney Transplant Recipients

It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 −24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67±0.3 and 1.36±0.73 × 103 l (P<0.00001) for tacrolimus and 0.42±0.17 and 0.84±0.46 × 103 l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)0–12 was 106.8±17.5 ng/ml × h compared with 133.3±42.2 ng/ml × h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC0–24 of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles. Clinical Pharmacology & Therapeutics (2007) 81, 228–234. doi:10.1038/sj.clpt.6100039; published online 27 December 2006