CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients.

Détails

ID Serval
serval:BIB_BC6922E390E7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients.
Périodique
Therapeutic Drug Monitoring
Auteur(s)
Crettol S., Venetz J.P., Fontana M., Aubert J.D., Pascual M., Eap C.B.
ISSN
1536-3694[electronic]
Statut éditorial
Publié
Date de publication
2008
Peer-reviewed
Oui
Volume
30
Numéro
6
Pages
689-699
Langue
anglais
Résumé
Cyclosporine is a substrate of cytochrome P450 (CYP) 3A and of the transporter ABCB1, for which polymorphisms have been described. In particular, CYP3A5 *3/*3 genotype results in the absence of CYP3A5 activity, whereas CYP3A7 *1/*1C genotype results in high CYP3A7 expression in adults. Log-transformed dose-adjusted cyclosporine trough concentration and daily dose per weight were compared 1, 3, 6, and 12 months after transplantation between CYP3A and ABCB1 genotypes in 73 renal (n = 64) or lung (n = 9) transplant recipients. CYP3A5 expressors (*1/*3 genotype; n = 8-10) presented significantly lower dose-adjusted cyclosporine trough concentrations (P < 0.05) and required significantly higher daily doses per weight (P < 0.01) than the nonexpressors (*3/*3 genotype; n = 55-59) 1, 3, 6, and 12 months after transplantation. In addition, 7 days after transplantation, more CYP3A5 expressors had uncorrected trough cyclosporine concentration below the target concentration of 200 ng/mL than the nonexpressors (odds ratio = 7.2; 95% confidence interval = 1.4-37.3; P = 0.009). CYP3A4 rs4646437C>T influenced cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. CYP3A7*1C carriers required a 1.4-fold to 1.6-fold higher cyclosporine daily dose during the first year after transplantation (P < 0.05). In conclusion, CYP3A4, CYP3A5, and CYP3A7 polymorphisms affect cyclosporine metabolism, and therefore, their genotyping could be useful, in association with therapeutic drug monitoring, to prospectively optimize cyclosporine prescription in transplant recipients. The administration of a CYP3A genotype-dependent cyclosporine starting dose should therefore be tested prospectively in a randomized controlled clinical trial to assess whether it leads to an improvement of the patients outcome after transplantation, with adequate immunosuppression and decreased toxicity.
Mots-clé
Adult, Aryl Hydrocarbon Hydroxylases, Cyclosporine, Cytochrome P-450 CYP3A, Dose-Response Relationship, Drug, Female, Genotype, Humans, Immunosuppressive Agents, Kidney Transplantation, Lung Transplantation, Male, Middle Aged, P-Glycoprotein, Polymorphism, Genetic
Pubmed
Web of science
Création de la notice
19/02/2008 17:00
Dernière modification de la notice
20/08/2019 15:30
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