P-glycoprotein (ABCB1), an ATP-binding-cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions (DDIs). ABCB1 has been suggested to interact with many antivirals used to treat HIV and/or chronic hepatitis C virus (HCV) infections. Using bidirectional transport experiments in Caco-2 cells and a recently established ex vivo model of accumulation in precision-cut intestinal slices (PCIS) prepared from rat ileum or human jejunum, we evaluated the potential of anti-HIV and anti-HCV antivirals to inhibit intestinal ABCB1. Lopinavir, ritonavir, saquinavir, atazanavir, maraviroc, ledipasvir, and daclatasvir inhibited the efflux of a model ABCB1 substrate, rhodamine 123 (RHD123), in Caco-2 cells and rat-derived PCIS. Lopinavir, ritonavir, saquinavir, and atazanavir also significantly inhibited RHD123 efflux in human-derived PCIS, while possible interindividual variability was observed in the inhibition of intestinal ABCB1 by maraviroc, ledipasvir, and daclatasvir. Abacavir, zidovudine, tenofovir disoproxil fumarate, etravirine, and rilpivirine did not inhibit intestinal ABCB1. In conclusion, using recently established ex vivo methods for measuring drug accumulation in rat- and human-derived PCIS, we have demonstrated that some antivirals have a high potential for DDIs on intestinal ABCB1. Our data help clarify the molecular mechanisms responsible for reported increases in the bioavailability of ABCB1 substrates, including antivirals and drugs prescribed to treat comorbidity. These results could help guide the selection of combination pharmacotherapies and/or suitable dosing schemes for patients infected with HIV and/or HCV.

• Klíčová slova
• Caco-2 cells, P-glycoprotein, antiviral drugs, drug-drug interactions, intestinal absorption, precision-cut intestinal slices, rhodamine 123,
• MeSH
• antivirové látky farmakologie   MeSH
• atazanavir sulfát farmakologie   MeSH
• benzimidazoly farmakologie   MeSH
• Caco-2 buňky účinky léků   metabolismus   MeSH
• fluoreny farmakologie   MeSH
• hepatitida C komplikace   farmakoterapie   virologie   MeSH
• HIV infekce komplikace   farmakoterapie   virologie   MeSH
• imidazoly farmakologie   MeSH
• karbamáty MeSH
• krysa rodu Rattus MeSH
• látky proti HIV farmakologie   MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• Lopinavir farmakologie   MeSH
• maravirok farmakologie   MeSH
• P-glykoprotein antagonisté a inhibitory   metabolismus   MeSH
• potkani Wistar MeSH
• pyrrolidiny MeSH
• ritonavir farmakologie   MeSH
• saquinavir farmakologie   MeSH
• senioři MeSH
• střeva účinky léků   MeSH
• valin analogy a deriváty   MeSH
• zidovudin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• atazanavir sulfát MeSH
• benzimidazoly MeSH
• daclatasvir MeSH Prohlížeč
• fluoreny MeSH
• imidazoly MeSH
• karbamáty MeSH
• látky proti HIV MeSH
• ledipasvir MeSH Prohlížeč
• Lopinavir MeSH
• maravirok MeSH
• P-glykoprotein MeSH
• pyrrolidiny MeSH
• ritonavir MeSH
• saquinavir MeSH
• valin MeSH
• zidovudin MeSH

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor used in first-line combination antiretroviral therapy (cART). It is usually administered with nucleoside reverse transcriptase inhibitors (NRTI), many of which are substrates of OCT uptake solute carriers (SLC22A) and MATE (SLC47A), P-gp (MDR1, ABCB1), BCRP (ABCG2), or MRP2 (ABCC2) efflux transporters. The aim of this study was to evaluate the inhibitory potential of efavirenz towards these transporters and investigate its effects on the pharmacokinetics and tissue distribution of a known Oct/Mate substrate, lamivudine, in rats. Accumulation and transport assays showed that efavirenz inhibits the uptake of metformin by OCT1-, OCT2- and MATE1-expressing MDCK cells and reduces transcellular transport of lamivudine across OCT1/OCT2- and MATE1-expressing MDCK monolayers. Only negligible inhibition of MATE2-K was observed in HEK-MATE2-K cells. Efavirenz also reduced the efflux of calcein from MDCK-MRP2 cells, but had a rather weak inhibitory effect on Hoechst 33342 accumulation in MDCK-MDR1 and MDCK-BCRP cells. An in vivo pharmacokinetic interaction study in male Wistar rats revealed that intravenous injection of efavirenz or the control Oct/Mate inhibitor cimetidine significantly reduced the recovery of lamivudine in urine and greatly increased lamivudine retention in the renal tissue. Co-administration with efavirenz or cimetidine also increased the AUC0-∞ value and reduced total body clearance of lamivudine. These data suggest that efavirenz is a potent inhibitor of OCT/Oct and MATE/Mate transporters. Consequently, it can engage in drug-drug interactions that reduce renal excretion of co-administered substrates and enhance their retention in the kidneys, potentially compromising therapeutic safety.

• MeSH
• alkyny MeSH
• benzoxaziny farmakologie   MeSH
• buňky MDCK MeSH
• cimetidin farmakologie   MeSH
• cyklopropany MeSH
• eliminace ledvinami MeSH
• HEK293 buňky MeSH
• inhibitory reverzní transkriptasy farmakokinetika   farmakologie   moč   MeSH
• krysa rodu Rattus MeSH
• lamivudin farmakokinetika   farmakologie   moč   MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• metformin metabolismus   farmakologie   MeSH
• plocha pod křivkou MeSH
• poločas MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty antagonisté a inhibitory   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům antagonisté a inhibitory   metabolismus   MeSH
• psi MeSH
• ROC křivka MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABCC2 protein, human MeSH Prohlížeč
• alkyny MeSH
• benzoxaziny MeSH
• cimetidin MeSH
• cyklopropany MeSH
• efavirenz MeSH Prohlížeč
• inhibitory reverzní transkriptasy MeSH
• lamivudin MeSH
• metformin MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH

Lamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employed in vitro accumulation and transport experiments on MDCK cells overexpressing drug efflux transporters, in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparent Km of 4.21 mM and Vmax of 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent with in vitro transport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.

• MeSH
• ABC transportéry metabolismus   MeSH
• biologický transport fyziologie   MeSH
• buněčné linie MeSH
• buňky MDCK MeSH
• krysa rodu Rattus MeSH
• lamivudin metabolismus   MeSH
• lidé MeSH
• P-glykoproteiny metabolismus   MeSH
• placenta metabolismus   MeSH
• potkani Wistar MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• psi MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCC2 protein, human MeSH Prohlížeč
• lamivudin MeSH
• P-glykoproteiny MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny přenášející organické kationty MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH