title: Comparison of bidirectional lamivudine and zidovudine transport using MDCK, MDCK-MDR1, and Caco-2 cell monolayers.
abstract: Bidirectional transport studies were conducted using Caco-2, MDCK, and MDCK-MDR1 to determine P-gp influences in lamivudine and zidovudine permeability and evaluate if zidovudine permeability changes with the increase of zidovudine concentration and/or by association of lamivudine. Transport of lamivudine and zidovudine separated and coadministrated across monolayers based on these cells were quantified using LC-MS-MS. Drug efflux by P-gp was inhibited using GG918. Bidirectional transport of lamivudine and zidovudine was performed across MDCK-MDR1 and Caco-2 cells. Statistically significant transport decrease in B --> A direction was observed using MDCK-MDR1 for zidovudine and MDCK-MDR1 and Caco-2 for lamivudine. Results show increased transport in B --> A and A --> B directions as concentration increases but data from P(app) increase in both directions for both drugs in Caco-2, decrease in MDCK, and does not change significantly in MDCK-MDR1. Zidovudine transport in A --> B direction increases when coadministrated with increasing lamivudine concentration but does not change significantly in B --> A direction. Zidovudine and lamivudine are P-gp substrates, but results assume that P-gp does not affect significantly lamivudine and zidovudine. Their transport in monolayers based on Caco-2 cells increase proportionally to concentration (in both directions) and zidovudine transport in Caco-2 cell monolayer does not show significant changes with lamivudine increasing concentrations.
authors.affiliation: Departamento de Farmácia (DEFAR), Escola de Farmácia, UFOP, Rua Costa Sena, 171 Centro, Ouro Preto, MG, Brazil. jacsouza@ef.ufop.br
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Souza
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Sílvia
authors.initials: S
authors.lastname: Storpirtis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D006801:Humans; D019259:Lamivudine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D015215:Zidovudine / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044005:Tetrahydroisoquinolines; D019259:Lamivudine; D015215:Zidovudine; C083501:Elacridar