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Le Kremlin-Bicêtre, France

Durand P.,Assistance Publique Hopitaux de Paris | Debray D.,Assistance Publique Hopitaux de Paris | Kolaci M.,University Paris - Sud | Bouligand J.,University Paris - Sud | And 8 more authors.
Pharmacogenomics | Year: 2013

Aim: Little information is available regarding the influence of CYP3A5 genetic polymorphisms on tacrolimus dose requirement in pediatric liver transplantation. Patients & methods: We performed a retrospective study among 179 pediatric liver recipients grafted between 2002 and 2009 in order to determine the influence of donor CYP3A5 genotype along with clinical variables on tacrolimus daily dose requirement during the first weeks following transplantation. Results: Mean stable tacrolimus daily dose requirement was higher among children who received a liver expressing CYP3A5 (carrying the CYPA3A5*1 allele) compared with those with a liver that did not express CYP3A5 (CYP3A5*3/*3 genotype): 0.29 ± 0.20 vs 0.18 ± 0.13 mg.kg-1.d-1, p = 0.005, respectively. A younger recipient age and fluconazole prescription were also significantly associated with tacrolimus daily dose requirement. Time to reach stable tacrolimus therapeutic trough concentrations was prolonged among patients with a CYP3A5-expressing graft (26 vs 21 days, p = 0.04). Conclusion: Donor CYP3A5 genotype partially explains tacrolimus dose requirement. Original submitted 30 January 2013; Revision submitted 2 May 201. © 2013 Future Medicine Ltd. Source


Michelon H.,Bicetre University Hospital | Konig J.,Friedrich - Alexander - University, Erlangen - Nuremberg | Durrbach A.,Friedrich - Alexander - University, Erlangen - Nuremberg | Quteineh L.,Bicetre University Hospital | And 8 more authors.
Pharmacogenomics | Year: 2010

Aims: This study aimed to determine the influence of gene candidates on mycophenolic acid (MPA) response during the first year of renal transplantation. Materials & methods: A total of 218 renal transplant recipients who received MPA from the first day of transplantation at a fixed dose of 2 g/day were genotyped for ABCB1, ABCC2, UGT2B7, UGT1A9, SLCO1B1, SLCO1B3 and IMPDH1 polymorphisms. Clinical end points were MPA-related adverse drug reactions (ADRs) and acute rejection episodes during the first year post-transplantation. Results: After correction for multiple statistical testing, SLCO1B1 (encoding the hepatic uptake transporter OATP1B1) was the only gene associated with MPA-related ADRs, showing a 75% risk reduction in favor of a protective effect of the SLCO1B1*5 allele (p = 0.002). In vitro experiments showed that MPA metabolites MPA-phenyl-glucuronide and MPA-acyl-glucuronide are substrates of OATP1B1. Their transport was decreased in the presence of the variant transporter (OATP1B1*5). Conclusion: These results suggest for the first time that carriers of the SLCO1B1*5 allele seem to be protected from MPA-related ADRs. © 2010 Future Medicine Ltd. Source


Carbonell N.,University Pierre and Marie Curie | Verstuyft C.,University Paris - Sud | Massard J.,University Pierre and Marie Curie | Letierce A.,Clinical Research Unit URC Paris Sud | And 6 more authors.
Clinical Pharmacology and Therapeutics | Year: 2010

Nonsteroidal anti-inflammatory drugs (NSAIDs), other than aspirin, are to some extent metabolized by cytochrome P450 2C9 (CYP2C9). The CYP2C9 359Leu (CYP2C9*3) loss-of-function allele could be a risk factor for acute upper gastrointestinal bleeding (AUGIB) related to the use of NSAIDs other than aspirin. To test this hypothesis, we performed a prospective, multicenter, case-case study in patients hospitalized for AUGIB related to the use of NSAIDs. A total of 131 patients had been treated with aspirin and 57 patients had been treated with an NSAID other than aspirin (non-ASP). In the aspirin group, 12 patients (9.2%) had the CYP2C9 359Leu allele as compared with 19 (33.3%) in the non-ASP group (odds ratio (OR) = 5.0; 95% confidence interval 2.2-11.1, P < 0.0001). In a multivariate analysis, CYP2C9 359Leu remained associated with the non-ASP group (OR = 7.2 (2.6-20.3), P = 0.0002) even though 40% of these patients were under treatment with antiulcer drugs at the time of admission. Therefore the results of the study support the hypothesis that the CYP2C9 359Leu allele is a robust risk factor for AUGIB related to the use of NSAIDs other than aspirin. © 2010 American Society for Clinical Pharmacology and Therapeutics. Source

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