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CYP3A5 Genotype Markedly Influences the Pharmacokinetics of Tacrolimus and Sirolimus in Kidney Transplant Recipients
Author(s) -
Renders L,
Frisman M,
Ufer M,
Mosyagin I,
Haenisch S,
Ott U,
Caliebe A,
Dechant M,
Braun F,
Kunzendorf U,
Cascorbi I
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100039
Subject(s) - tacrolimus , sirolimus , cyp3a5 , trough concentration , pharmacokinetics , trough level , medicine , therapeutic drug monitoring , pharmacology , urology , creatinine , renal function , area under the curve , gastroenterology , chemistry , transplantation , genotype , biochemistry , gene
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 × 10 3 l ( P <0.00001) for tacrolimus and 0.42±0.17 and 0.84±0.46 × 10 3 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 AUC 0–24 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