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CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study.

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Haufroid, Vincent [UCL] De Meyer, Martine [UCL] Wallemacq, Pierre [UCL] Van Kerckhove, Valérie [UCL] Elens, Laure [UCL] Lison, Dominique [UCL] Mourad, Michel [UCL]

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-infinity) 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.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès restreint
Publication date 2006
Journal information "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons" - Vol. 6, no. 11, p. 2706-13 (2006)
Peer reviewed yes
issn 1600-6135
Publication status Publié
Affiliations UCL - Cliniques universitaires Saint-Luc
UCL - MD/ESP - Ecole de santé publique
UCL - MD/CHIR - Département de chirurgie
MESH Subject Area Under Curve ; Cytochrome P-450 Enzyme System - genetics ; Genotype ; Human Experimentation ; Humans ; Immunosuppressive Agents - pharmacokinetics ; Kidney Transplantation - immunology - physiology ; Mass Spectrometry ; Organic Anion Transporters - genetics ; P-Glycoprotein ; Polymorphism, Genetic ; Tacrolimus - pharmacokinetics
Links
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Bibliographic reference Haufroid, Vincent ; De Meyer, Martine ; Wallemacq, Pierre ; Van Kerckhove, Valérie ; Elens, Laure ; et. al. CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study.. In: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Vol. 6, no. 11, p. 2706-13 (2006)
Permanent URL http://hdl.handle.net/2078.1/10754