Premium
CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study
Author(s) -
Haufroid V.,
Wallemacq P.,
VanKerckhove V.,
Elens L.,
De Meyer M.,
Eddour D. C.,
Malaise J.,
Lison D.,
Mourad M.
Publication year - 2006
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2006.01518.x
Subject(s) - cyp3a5 , pharmacokinetics , medicine , tacrolimus , trough level , transplantation , pharmacology , therapeutic drug monitoring , gastroenterology , kidney transplantation , pharmacogenetics , trough concentration , genotype , urology , biology , biochemistry , gene
Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G > A, CYP3A5*3 ; 14690A > G, CYP3A5*6 ) and drug transporter ABCB1 (1236C > T; 2677G > T/A; 3435C > T) are known to influence tacrolimus (Tac) dose requirements and trough blood levels in stable transplant patients. In a group of 19 volunteers selected with relevant genotypes among a list of 221 adult renal transplant candidates, we evaluated whether consideration of CYP3A5 and ABCB1 genetic polymorphisms could explain the interindividual variability in Tac pharmacokinetics after the first administration of a standard dose (0.1 mg/kg body weight twice a day). Lower area under the time versus blood concentration curves (AUC) or lower trough concentrations were observed among CYP3A5 expressors (n = 9) than among nonexpressors (n = 10) using two different analytical methods for Tac determination (liquid chromatography with tandem mass spectrometry (LC‐MS/MS) and immunoassay). The median AUC 0−∞ was 2.6‐ and 2.1‐fold higher in nonexpressors for LC‐MS/MS and immunologic methods, respectively. No difference was observed in Tac pharmacokinetic parameters in relation to ABCB1 polymorphisms. In conclusion, our study confirms the very significant effect of CYP3A5 polymorphism early after the first administration of Tac. It also provides a strong argument for a doubling of the loading dose in patients early identified a priori on the transplantation list as possessing at least one CYP3A5*1 allele.