<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Laure Elens</style></author><author><style face="normal" font="default" size="100%">Arnaud Capron</style></author><author><style face="normal" font="default" size="100%">Valérie Van Kerckhove</style></author><author><style face="normal" font="default" size="100%">Jan Lerut</style></author><author><style face="normal" font="default" size="100%">Michel Mourad</style></author><author><style face="normal" font="default" size="100%">Lison, Dominique</style></author><author><style face="normal" font="default" size="100%">Wallemacq, Pierre</style></author><author><style face="normal" font="default" size="100%">Haufroid, Vincent</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">1199G&gt;A and 2677G&gt;T/A polymorphisms of ABCB1 independently affect tacrolimus concentration in hepatic tissue after liver transplantation.</style></title><secondary-title><style face="normal" font="default" size="100%">Pharmacogenet Genomics</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Aryl Hydrocarbon Hydroxylases</style></keyword><keyword><style  face="normal" font="default" size="100%">ATP Binding Cassette Transporter, Subfamily B</style></keyword><keyword><style  face="normal" font="default" size="100%">ATP Binding Cassette Transporter, Subfamily B, Member 1</style></keyword><keyword><style  face="normal" font="default" size="100%">Cytochrome P-450 CYP3A</style></keyword><keyword><style  face="normal" font="default" size="100%">Cytochrome P-450 Enzyme System</style></keyword><keyword><style  face="normal" font="default" size="100%">Drug Administration Schedule</style></keyword><keyword><style  face="normal" font="default" size="100%">Gene Frequency</style></keyword><keyword><style  face="normal" font="default" size="100%">Genotype</style></keyword><keyword><style  face="normal" font="default" size="100%">Graft Rejection</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Immunosuppressive Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">Linear Models</style></keyword><keyword><style  face="normal" font="default" size="100%">Liver</style></keyword><keyword><style  face="normal" font="default" size="100%">Liver Transplantation</style></keyword><keyword><style  face="normal" font="default" size="100%">Liver-Specific Organic Anion Transporter 1</style></keyword><keyword><style  face="normal" font="default" size="100%">Organic Anion Transporters</style></keyword><keyword><style  face="normal" font="default" size="100%">Polymorphism, Genetic</style></keyword><keyword><style  face="normal" font="default" size="100%">Purines</style></keyword><keyword><style  face="normal" font="default" size="100%">Pyrimidines</style></keyword><keyword><style  face="normal" font="default" size="100%">Tacrolimus</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2007</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2007 Oct</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">17</style></volume><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;b&gt;OBJECTIVE: &lt;/b&gt;Tacrolimus is an immunosuppressive drug widely used in hepatic transplantation to avoid graft rejection. Its pharmacokinetics is characterized by a large interindividual variability requiring the use of therapeutic drug monitoring in daily clinical practice. Some genetic polymorphisms in biotransformation enzymes or transporter proteins, such as CYP3A5 and P-glycoprotein (ABCB1), in donors and/or recipients, appear as important determinants of the Tac blood pharmacokinetics. A recent study has shown that Tac hepatic tissue concentrations vary greatly among patients and are well correlated with graft outcome. The aim of our study was to investigate the effect of genetic polymorphisms in biotransformation enzymes (CYP3A5 and CYP3A7) or in their regulatory protein pregnane X receptor as well as in transporter proteins (ABCB1 and OATP-C) on Tac pharmacokinetics in liver transplant patients and more specifically on Tac hepatic concentrations.&lt;/p&gt;

&lt;p&gt;&lt;b&gt;METHODS: &lt;/b&gt;One hundred and fifty liver donors were genotyped for 13 different polymorphisms. Tac blood and hepatic concentrations were compared according to hepatic genotypes.&lt;/p&gt;

&lt;p&gt;&lt;b&gt;RESULTS AND CONCLUSION: &lt;/b&gt;We confirmed that Tac dose requirement (on the basis of blood therapeutic drug monitoring) was higher among patients expressing hepatic CYP3A5 (at least one CYP3A5*1 allele) compared with patients who did not (CYP3A5*3/*3). Hepatic expression of CYP3A5, however, did not seem to influence Tac hepatic concentrations. In contrast, ABCB1 genetic polymorphisms significantly influenced Tac hepatic concentrations, whereas their impact on blood concentrations seemed negligible. Among these ABCB1 polymorphisms, the 1199G&amp;gt;A and 2677G&amp;gt;T/A single nucleotide polymorphisms seemed to reduce the activity of P-gp on Tac. As Tac hepatic concentrations have been significantly related to the graft outcome, it might be interesting, in the future, to genotype donors for ABCB1 polymorphisms to better individualize the Tac immunosuppressive therapy in hepatic transplantation.&lt;/p&gt;
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