Influence of efflux transporters on liver, bile and brain disposition of amitriptyline in mice.
The aim of this work was to clarify the role of Abcb1 and the possible involvement of Abcc2 and Abcg2 in liver, bile and brain disposition of amitriptyline (AMI). AMI was administrated to Abcb1a deficient mice (n=36): CF1 (-/-) and CF1 (+/+) mice received via intraperitoneal route (i.p.) 5 mg/kg AMI and CF1 (+/+) mice received i.p. 5 mg/kg AMI+100 mg/kg quinidine (Abcb1 inhibitor). Then, Swiss mice (n=24) received i.p. 5 mg/kg AMI alone and in association with 200 mg/kg novobiocin (Abcg2 inhibitor), 20 mg/kg probenecid (Abcc2 inhibitor) and 100 mg/kg quinidine. Plasma concentrations of AMI were not influenced by novobiocin, probenecid and the lack of Abcb1, but were significantly increased by quinidine, resulting from the inhibition of hydroxylation mediated by CYP2D6. Brain distribution of AMI was not influenced by the lack of Abcb1 but was slightly significant with quinidine and not with novobiocin and probenecid. At the hepato-biliary interface, we showed the involvement of Abcb1, Abcc2 and Abcg2; indeed, AMI concentration was increased in liver and decreased in bile, where quinidine is the strongest inhibitor, followed by probenecid and novobiocin. These results show that in brain the effect of Abcb1, Abcc2 and Abcg2 should be negligible and that at the hepato-biliary level, Abcb1 plays a predominant role compared to Abcc2 and Abcg2.
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Unité UPRES EA 3892, Laboratoire de Pharmacie Galénique, Biopharmacie et Pharmacie Clinique Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, 2 avenue du Pr Léon Bernard 35043 Rennes cedex, France.
Chevanne
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Le Corre
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D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000639:Amitriptyline / Q000493:pharmacokinetics*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D005260:Female; D007274:Injections, Intraperitoneal; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009675:Novobiocin / Q000494:pharmacology; D011339:Probenecid / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000639:Amitriptyline; D000929:Antidepressive Agents, Tricyclic; D019389:Cytochrome P-450 CYP2D6; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009675:Novobiocin; D011339:Probenecid; D011802:Quinidine; C501412:Abcg2 protein, mouse; C507084:Abcb1b protein, mouse