- Klíčová slova
- tenofovir alafenamid fumarát, GS-US-292-0104, GS-US-292-0111, GS-US-292-0112, GS-US-292-0109,
- MeSH
- adenin * analogy a deriváty aplikace a dávkování farmakokinetika terapeutické užití MeSH
- antiretrovirové látky terapeutické užití MeSH
- HIV infekce farmakoterapie MeSH
- kobicistat terapeutické užití MeSH
- kombinace léků elvitegravir, cobicistat, emtricitabin a tenofovir aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- látky proti HIV terapeutické užití MeSH
- lidé MeSH
- přenašeče organických aniontů MeSH
- randomizované kontrolované studie jako téma MeSH
- tenofovir * farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND AND AIMS: Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of glomerular filtration with active tubular transport. Nonalcoholic steatohepatitis is a variable in drug disposition, yet the impact on renal transport processes has yet to be fully understood. The goal of this study was to determine the effect of nonalcoholic steatohepatitis on the pharmacokinetics of adefovir in rats given a control or methionine and choline deficient diet to induce nonalcoholic steatohepatitis. METHODS: Animals received a bolus dose of 7mg/kg (35μCi/kg) [(3)H] adefovir with consequent measurement of plasma and urine concentrations. Inulin clearance was used to determine glomerular filtration rate. RESULTS: Methionine and choline deficient diet-induced nonalcoholic steatohepatitis prolonged the elimination half-life of adefovir. This observation occurred in conjunction with reduced distribution volume and hepatic levels of adefovir. Notably, despite these changes, renal clearance and overall clearance were not changed, despite markedly reduced glomerular filtration rate in nonalcoholic steatohepatitis. Alteration of glomerular filtration rate was fully compensated for by a significant increase in tubular secretion of adefovir. Analysis of renal transporters confirmed transcriptional up-regulation of Mrp4, the major transporter for adefovir tubular secretion. CONCLUSIONS: This study demonstrates changes to glomerular filtration and tubular secretion that alter pharmacokinetics of adefovir in nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis-induced changes in renal drug elimination processes could have major implications in variable drug response and the potential for toxicity.
- MeSH
- adenin analogy a deriváty farmakokinetika MeSH
- cholin aplikace a dávkování MeSH
- dieta MeSH
- hodnoty glomerulární filtrace MeSH
- inhibitory reverzní transkriptasy farmakokinetika MeSH
- krysa rodu rattus MeSH
- ledviny účinky léků metabolismus MeSH
- methionin aplikace a dávkování MeSH
- nealkoholová steatóza jater metabolismus MeSH
- organofosfonáty farmakokinetika MeSH
- potkani Sprague-Dawley MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE AND DESIGN: Tenofovir (TFV) is used in pregnant women as a part of combination antiretroviral treatment to prevent mother-to-child transmission of HIV infection. We aimed to detect whether TFV and/or its prodrug, tenofovir disoproxil fumarate (TDF), are substrates of ATP-binding cassette (ABC) transporters that are functionally expressed in the placenta, namely P-glycoprotein (ABCB1/MDR1), Breast Cancer Resistance Protein (ABCG2/BCRP) and Multidrug Resistance-Associated Protein 2 (ABCC2/MRP2). We employed in-vitro cell-based assays and in-situ animal model to assess possible role of the efflux transporters in transplacental pharmacokinetics of TFV and TDF. METHODS: In-vitro transport assays were performed in MDCKII cells transduced with human ABCB1, ABCG2 or ABCC2. To quantify the effect of these transporters on TFV/TDF transplacental passage, we employed the in-situ model of dually perfused rat term placenta in open and closed setup. RESULTS: In-vitro assays revealed that TDF is a dual substrate of ABCB1 and ABCG2 but not of ABCC2. In contrast, TFV transport was not influenced by any of these transporters. Applying concentration-dependent studies and selective inhibitors, we further confirmed these findings in situ on the organ level; both ABCB1 and ABCG2 limited mother-to-fetus transfer of TDF whereas TFV transplacental passage was not affected by these ABC transporters. CONCLUSION: We propose limited mother-to-fetus transport of both TFV and TDF. While placental transport of TFV is restricted passively, by physical-chemical properties of the molecule, mother-to-fetus passage of TDF is actively hindered by placental ABCB1 and ABCG2 transporters, pumping this compound from trophoblast back to maternal circulation.
- MeSH
- ABC transportéry metabolismus MeSH
- adenin analogy a deriváty metabolismus farmakokinetika MeSH
- buněčné linie MeSH
- krysa rodu rattus MeSH
- látky proti HIV metabolismus farmakokinetika MeSH
- lidé MeSH
- nádorové proteiny metabolismus MeSH
- organofosfonáty metabolismus farmakokinetika MeSH
- P-glykoprotein metabolismus MeSH
- potkani Wistar MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Acyclic nucleotide analogue PMEG represents promising drug candidate against lymphomas. In the present work we describe the ability of PMEG to induce resistance and we elucidate the mechanisms involved in this process. CCRF-CEM T-lymphoblastic cells resistant to either PMEG or its 6-amino congener PMEDAP were prepared and assayed for the expression of membrane transporters, PMEG and PMEDAP uptake and intracellular metabolism. Genes for guanylate kinase (GUK) and adenylate kinase (AK) isolated from PMEG- and PMEDAP-resistant cells were sequenced and cloned into mammalian expression vectors. PMEG-resistant cells were transfected with GUK vectors and catalytic activities of GUKs isolated from PMEG-sensitive and resistant cells were compared. PMEG phosphorylation to PMEG mono- and diphosphate was completely impaired in resistant cells. GUK obtained from PMEG-resistant cells revealed two point mutations S(35)N V(168)F that significantly suppressed its catalytic activity. Transfection of resistant cells with wtGUK led to the recovery of phosphorylating activity as well as sensitivity towards PMEG cytotoxicity. No differences in PMEG uptake have been found between sensitive and resistant cells. In contrast to GUK no changes in primary sequence of AK isolated from PMEDAP resistant cells were identified. Therefore, resistance induced by PMEDAP appears to be conferred by other mechanisms. In conclusion, we have identified GUK as the sole molecular target for the development of acquired resistance to the cytotoxic nucleotide PMEG. Therefore, PMEG is unlikely to cause cross-resistance in combination therapeutic protocols with most other commonly used anticancer drugs.
- MeSH
- adenin analogy a deriváty farmakokinetika farmakologie MeSH
- adenylátkinasa genetika MeSH
- antitumorózní látky farmakologie MeSH
- bodová mutace MeSH
- chemorezistence MeSH
- fosforylace MeSH
- guanin analogy a deriváty farmakokinetika farmakologie MeSH
- guanylátkinasy genetika MeSH
- kultivované buňky MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- organofosforové sloučeniny farmakokinetika farmakologie MeSH
- sekvence aminokyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The objective of this work was to investigate feasibility of transdermal and dermal delivery of adefovir (9-(2-phosphonomethoxyethyl)adenine), a broad-spectrum antiviral from the class of acyclic nucleoside phosphonates. Transport of 2% adefovir through and into porcine skin and effects of various solvents, pH, and permeation enhancers were studied in vitro using Franz diffusion cell. From aqueous donor samples, adefovir flux through the skin was 0.2-5.4 microg/cm2/h with greatest permeation rate at pH 7.8. The corresponding adefovir skin concentrations reached values of 120-350 microg/g of tissue. Increased solvent lipophilicity resulted in higher skin concentration but had only minor effect on adefovir flux. A significant influence of counter ions on both transdermal and dermal transport of adefovir zwitterion was observed at pH 3.4. Permeation enhancer dodecanol was ineffective, 1-dodecylazepan-2-one (Azone) and dodecyl 2-(dimethylamino)propionate (DDAIP) showed moderate activity. The highest adefovir flux (11.3+/-3.6 microg/cm2/h) and skin concentration (1549+/-416 microg/g) were achieved with 1% Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycarbonyl)pentylcarbamate) at pH 4. This study suggests that, despite its hydrophilic and ionizable nature, adefovir can be successfully delivered through the skin.
- MeSH
- adenin analogy a deriváty aplikace a dávkování farmakokinetika MeSH
- antivirové látky aplikace a dávkování farmakokinetika MeSH
- aplikace kožní MeSH
- financování organizované MeSH
- koncentrace vodíkových iontů MeSH
- kožní absorpce účinky léků MeSH
- lidé MeSH
- organofosfonáty aplikace a dávkování farmakokinetika MeSH
- permeabilita MeSH
- pomocné látky MeSH
- rozpouštědla MeSH
- systémy cílené aplikace léků MeSH
- techniky in vitro MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
- MeSH
- acetylcholin farmakokinetika farmakologie MeSH
- adenin * farmakokinetika farmakologie MeSH
- adenosinmonofosfát * farmakokinetika farmakologie MeSH
- adenosintrifosfát * farmakokinetika farmakologie MeSH
- experimenty na zvířatech MeSH
- hodnocení léčiv metody využití MeSH
- kočky MeSH
- králíci MeSH
- papírová chromatografie metody využití MeSH
- shiga toxiny agonisté MeSH
- statistika jako téma MeSH
- žáby MeSH
- zvířata MeSH
- Check Tag
- kočky MeSH
- králíci MeSH
- zvířata MeSH
