TY - JOUR
T1 - CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients
AU - Renders, L.
AU - Frisman, M.
AU - Ufer, M.
AU - Mosyagin, I.
AU - Haenisch, S.
AU - Ott, U.
AU - Caliebe, A.
AU - Dechant, M.
AU - Braun, F.
AU - Kunzendorf, U.
AU - Cascorbi, I.
PY - 2007/2
Y1 - 2007/2
N2 - 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 I (P < 0.00001) for tacrolimus and 0.42 ± 0.17 and 0.84 ± 0.46 × 103 I (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.
AB - 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 I (P < 0.00001) for tacrolimus and 0.42 ± 0.17 and 0.84 ± 0.46 × 103 I (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.
UR - http://www.scopus.com/inward/record.url?scp=33846632909&partnerID=8YFLogxK
U2 - 10.1038/sj.clpt.6100039
DO - 10.1038/sj.clpt.6100039
M3 - Article
C2 - 17192769
AN - SCOPUS:33846632909
SN - 0009-9236
VL - 81
SP - 228
EP - 234
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 2
ER -