Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.
- Klíčová slova
- ABC transporters, abacavir, drug transporter, drug-drug interactions, oral bioavailability, pharmacokinetics, rilpivirine,
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- biologický transport fyziologie MeSH
- buněčné linie MeSH
- buňky MDCK MeSH
- Caco-2 buňky MeSH
- dideoxynukleosidy metabolismus farmakologie MeSH
- inhibitory reverzní transkriptasy metabolismus farmakologie MeSH
- intestinální absorpce fyziologie MeSH
- krysa rodu Rattus MeSH
- lamivudin metabolismus farmakologie MeSH
- lékové interakce fyziologie MeSH
- lidé MeSH
- membránové transportní proteiny metabolismus MeSH
- nádorové buněčné linie MeSH
- P-glykoprotein metabolismus MeSH
- potkani Wistar MeSH
- psi MeSH
- rilpivirin metabolismus farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- abacavir MeSH Prohlížeč
- ABC transportér z rodiny G, člen 2 MeSH
- dideoxynukleosidy MeSH
- inhibitory reverzní transkriptasy MeSH
- lamivudin MeSH
- membránové transportní proteiny MeSH
- P-glykoprotein MeSH
- rilpivirin MeSH
1. Emtricitabine is a nucleoside reverse transcriptase inhibitor used in combination antiretroviral therapy of HIV (cART). Although active transport mechanisms are believed to mediate tubular secretion of the drug into urine, the responsible transporter and its potential to cause pharmacokinetic drug--drug interactions (DDI) has not been identified so far. The aim of this study was to investigate whether drug transporters P-gp (ABCB1), BCRP (ABCG2), MRP2 (ABCC2), OCT1 (SLC22A1), OCT2 (SLC22A2) or MATE1 (SLC47A1) can mediate active transcellular transfer of emtricitabine. 2. We employed transport assays in polarized monolayers of MDCK cells stably expressing P-gp, BCRP, MRP2, OCT1, OCT2 and/or MATE1. Among the transporters studied only MATE1 accelerated basal-to-apical transport of emtricitabine over a wide range of concentrations (6 nM to 1 mM). The transport was enhanced by an oppositely directed pH gradient and significantly reduced (p < 0.001) at low temperature in MDCK-MATE1, MDCK-OCT1/MATE1 and MDCK-OCT2/MATE1 cells. Co-administration of cimetidine or ritonavir decreased MATE1-mediated transport of emtricitabine by up to 42 and 39%, respectively (p < 0.01) and augmented intracellular accumulation of emtricitabine (p < 0.05). 3. We demonstrate emtricitabine as a substrate of MATE1 and suggest that MATE1 might cause DDI between emtricitabine and other co-administrated drugs including antiretrovirals.
- Klíčová slova
- Cimetidine *, MDCK cells *, combination antiretroviral therapy *, drug–drug interactions *, pharmacokinetics *, ritonavir *,
- MeSH
- buňky MDCK MeSH
- emtricitabin metabolismus MeSH
- inhibitory reverzní transkriptasy metabolismus MeSH
- P-glykoprotein metabolismus MeSH
- proteiny přenášející organické kationty metabolismus MeSH
- psi MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- emtricitabin MeSH
- inhibitory reverzní transkriptasy MeSH
- P-glykoprotein MeSH
- proteiny přenášející organické kationty MeSH
To elucidate the structure-geometry-activity relationship in diarylpyrimidine family (DAPYs) containing carbonyl linker between the central pyrimidine core and phenyl type B-arm, a series of (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones was designed, prepared and tested for their anti-HIV-1 activity. The carbonyl linker bearing B phenyl arm was successfully attached at both C-2 and C-4 positions of the central pyrimidine ring using a new synthetic approach. Further modifications of target compounds are present at C-5 position of the pyrimidine ring. In vitro anti-HIV-1 activity study performed on a series of 22 compounds confirmed the crucial importance of both conformational rigidity between phenyl B arm and the pyrimidine core linked through the carbonyl bridge, as well as presence of fluoro substituents in ortho-positions of phenyl B moiety. The most potent derivative of the series, compound 17, having almost perpendicular angle within the two planes made from the B aromatic arm and the pyrimidine ring, exhibited low nanomolar anti-HIV-1 activity (EC50 = 4 nM) with no significant toxicity (CC50 > 57.1 μM).
- Klíčová slova
- Diarylpyrimidine (DAPY), Etravirine, Human immunodeficiency virus (HIV), NNRTIs, Non-nucleoside reverse transcriptase inhibitors, Rilpivirine,
- MeSH
- HIV reverzní transkriptasa antagonisté a inhibitory chemie metabolismus MeSH
- HIV-1 účinky léků enzymologie MeSH
- inhibitory reverzní transkriptasy chemie metabolismus farmakologie MeSH
- konformace proteinů MeSH
- pyrimidiny chemie metabolismus farmakologie MeSH
- racionální návrh léčiv * MeSH
- simulace molekulového dockingu MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- HIV reverzní transkriptasa MeSH
- inhibitory reverzní transkriptasy MeSH
- pyrimidiny MeSH
Tenofovir diphosphate (PMPApp) is a weak inhibitor of DNA polymerases (pol) alpha, delta, and epsilon*, with values for the Ki for PMPApp ((PMPApp)Ki) relative to the Km for dATP ((dATP)Km) of 10.2, 10.2, and 15.2, respectively. Its incorporation into DNA was about 1,000-fold less efficient than that of dATP, with (PMPApp)Km values 350-, 2,155-, and 187-fold higher than (dATP)Km values for pol alpha, delta, and epsilon*, respectively.
- MeSH
- adenin analogy a deriváty metabolismus farmakologie MeSH
- DNA-dependentní DNA-polymerasy metabolismus MeSH
- DNA-polymerasa I antagonisté a inhibitory metabolismus MeSH
- DNA-polymerasa II antagonisté a inhibitory metabolismus MeSH
- DNA-polymerasa III antagonisté a inhibitory metabolismus MeSH
- inhibitory reverzní transkriptasy metabolismus farmakologie MeSH
- inhibitory syntézy nukleových kyselin * MeSH
- krysa rodu Rattus MeSH
- látky proti HIV metabolismus farmakologie MeSH
- organofosfonáty * MeSH
- organofosforové sloučeniny metabolismus farmakologie MeSH
- tenofovir MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adenin MeSH
- DNA-dependentní DNA-polymerasy MeSH
- DNA-polymerasa I MeSH
- DNA-polymerasa II MeSH
- DNA-polymerasa III MeSH
- inhibitory reverzní transkriptasy MeSH
- inhibitory syntézy nukleových kyselin * MeSH
- látky proti HIV MeSH
- organofosfonáty * MeSH
- organofosforové sloučeniny MeSH
- tenofovir MeSH
