title: Induction of multiple drug transporters by efavirenz.
abstract: Efavirenz, an important component of human immunodeficiency virus 1 (HIV-1) therapy, causes substantial drug interactions as an inducer of cytochromes and the transporter ABCB1. So far its effect on the expression of other transporters is unknown. We therefore investigated the effect of long-term exposure of cells to efavirenz on expression of a large number of important drug transporters and on cell proliferation as a surrogate of intracellular availability. LS180 cells were used as a surrogate for the major site of drug interactions and Jurkat cells were used as a surrogate for the main target cells of HIV therapy. Cells were treated with efavirenz over 4 weeks and mRNA expression of drug transporters was repeatedly quantified. After 4 weeks, efavirenz significantly up-regulated the mRNA of ABCB1, ABCG2, ABCC2, ABCC3, ABCC5, and SLCO3A1 in LS180 cells and ABCG2, ABCC1, ABCC4, ABCC5, and SLCO2B1 in Jurkat cells. However these changes in transporter expression did not influence cell proliferation indicating that intracellular efavirenz concentrations were likely not altered. Efavirenz induces mRNA expression of several drug transporters critically modulating the kinetics of other drugs. While these expressional changes will most likely not influence the efficiency of efavirenz itself, they might change the effect of other co-administered drugs.
authors.affiliation: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Germany. johanna.weiss@med.uni-heidelberg.de
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Melanie
authors.initials: M
authors.lastname: Herzog
authors.forename: Sonja
authors.initials: S
authors.lastname: König
authors.forename: Caroline Henrike
authors.initials: CH
authors.lastname: Storch
authors.forename: Nahal
authors.initials: N
authors.lastname: Ketabi-Kiyanvash
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C098320:efavirenz