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CYP3A7, CYP3A5, CYP3A4, and ABCB1 Genetic Polymorphisms, Cyclosporine Concentration, and Dose Requirement in Transplant Recipients

Crettol, Séverine PhD*; Venetz, Jean-Pierre MD; Fontana, Massimiliano MD; Aubert, John-David MD; Pascual, Manuel MD; Eap, Chin B PhD*‡

doi: 10.1097/FTD.0b013e31818a2a60
Original Article
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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.

From the *Unité de Biochimie et de Psychopharmacologie Clinique, Centre de Neurosciences Psychiatriques, Département de Psychiatrie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Hôpital de Cery, Prilly-Lausanne; †Centre de Transplantation, Centre Hospitalier Universitaire Vaudois et Université de Lausanne; and Ecole de Pharmacie, Université de Genève, Université de Lausanne, Lausanne, Switzerland.

Received for publication August 22, 2007; accepted August 7, 2008.

Part of this work was presented as an oral communication at the World Transplant Congress 2006 (July 22-27, 2006 in Boston, MA).

Supported in part by the Swiss National Research Foundation (project 3200-065427.01) and by a grant from Novartis, Switzerland.

The funding sources had no role in the design, conduct, and reporting of the study or in the decision to submit the manuscript for publication.

Correspondence: Chin B. Eap, PhD, Unité de Biochimie et de Psychopharmacologie Clinique, Centre de Neurosciences Psychiatriques, Département de Psychiatrie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Hôpital de Cery, CH-1008 Prilly-Lausanne, Switzerland (e-mail: chin.eap@chuv.ch).

© 2008 Lippincott Williams & Wilkins, Inc.