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• W2044616618 abstract "Background: Tacrolimus (Tac) metabolism is mainly mediated by the cytochrome P450 3A (CYP3A) subfamily. Recently, it has been reported that kidney transplant recipients carrying the CYP3A4*22 decrease-of-function allele require lower Tac doses and are more at risk of Tac overexposure than CYP3A4*1/*1 patients. This effect was shown to be independent of the CYP3A5*3 allelic status. However, the pharmacokinetic (PK) parameters assessed in previous studies were limited on single time point whole blood trough concentrations (C0) during routine follow-up of the patient after transplantation. Methods: Our study investigates the impact of the CYP3A4*22 allele on Tac PK [C0, area under the time vs concentration curve (AUC0–12h), apparent clearance (Cl/F), Cmax, and dose requirement], time to achieve target C0, and creatinine clearance (CrCl) in 96 kidney transplant recipients considering the 2 first weeks after the graft. All patients were genotyped for both the CYP3A4*22 and the CYP3A5*3 polymorphisms. Results: CYP3A4*22 carriers had higher Tac C0 during the first week with significant longer exposures to C0 > 15 ng/mL. These patients showed reduced Tac Cl/F but higher dose-adjusted AUC0–12h and Cmax and were at increased risk of C0 > 20 ng/mL. These effects were independent from CYP3A5*3 genotype: clustering patients according to both CYP3A4*22 and CYP3A5*3 allelic status did increase the predictive value of the genotype to explain interindividual differences in Tac PK. During the second week after transplantation, CrCl was on average 9.5 mL/min higher for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (P = 0.007), suggesting that Tac overexposure in CYP3A4*22 carriers might provide a renal function benefit. Conclusions: Our study confirms the decreased CYP3A4 activity toward Tac for CYP3A4*22 carriers early after transplantation and provides evidence for refining genotype-based dosage by adding the CYP3A4*22 genotype information to the CYP3A5*3 allelic status." @default.
• W2044616618 created "2016-06-24" @default.
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• W2044616618 date "2013-10-01" @default.
• W2044616618 modified "2023-10-11" @default.
• W2044616618 title "Impact of CYP3A4*22 Allele on Tacrolimus Pharmacokinetics in Early Period After Renal Transplantation" @default.
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• W2044616618 doi "https://doi.org/10.1097/ftd.0b013e318296045b" @default.
• W2044616618 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24052064" @default.
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