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CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study.
Am J Transplant. 2006 Nov; 6(11):2706-13.AJ

Abstract

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.

Authors+Show Affiliations

Industrial and Environmental Toxicology Unit, Université catholique de Louvain, St. Luc Hospital, Brussels, Belgium. haufroid@toxi.ucl.ac.beNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17049058

Citation

Haufroid, V, et al. "CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines From an Experimental Study." American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, vol. 6, no. 11, 2006, pp. 2706-13.
Haufroid V, Wallemacq P, VanKerckhove V, et al. CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. Am J Transplant. 2006;6(11):2706-13.
Haufroid, V., Wallemacq, P., VanKerckhove, V., Elens, L., De Meyer, M., Eddour, D. C., Malaise, J., Lison, D., & Mourad, M. (2006). CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 6(11), 2706-13.
Haufroid V, et al. CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines From an Experimental Study. Am J Transplant. 2006;6(11):2706-13. PubMed PMID: 17049058.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. AU - Haufroid,V, AU - Wallemacq,P, AU - VanKerckhove,V, AU - Elens,L, AU - De Meyer,M, AU - Eddour,D C, AU - Malaise,J, AU - Lison,D, AU - Mourad,M, PY - 2006/10/20/pubmed PY - 2006/12/9/medline PY - 2006/10/20/entrez SP - 2706 EP - 13 JF - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons JO - Am J Transplant VL - 6 IS - 11 N2 - 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. SN - 1600-6135 UR - https://www.unboundmedicine.com/medline/citation/17049058/CYP3A5_and_ABCB1_polymorphisms_and_tacrolimus_pharmacokinetics_in_renal_transplant_candidates:_guidelines_from_an_experimental_study_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1600-6135&date=2006&volume=6&issue=11&spage=2706 DB - PRIME DP - Unbound Medicine ER -