Myricetin (MYR) and ampelopsin (AMP, or dihydromyricetin) are flavonoid aglycones found in certain plants and dietary supplements. During the presystemic biotransformation of flavonoids, mainly sulfate and glucuronide derivatives are produced, which are the dominant metabolites in the circulation. In this study, we tested the interactions of MYR, myricetin-3'-O-sulfate (M3'S), AMP, and ampelopsin-4'-O-sulfate (A4'S) with human serum albumin (HSA), cytochrome P450 enzymes (CYPs), and organic anion-transporting polypeptides (OATPs) using in vitro models, including the recently developed method for measuring flavonoid levels in living cells. M3'S and MYR bound to albumin with high affinity, and they showed moderate displacing effects versus the Site I marker warfarin. MYR, M3'S, AMP, and A4'S exerted no or only minor inhibitory effects on CYP2C9, CYP2C19, and CYP3A4 enzymes. M3'S and MYR caused considerable inhibitory actions on OATP1B1 at low micromolar concentrations (IC50 = 1.7 and 6.4 μM, respectively), while even their nanomolar levels resulted in strong inhibitory effects on OATP2B1 (IC50 = 0.3 and 0.4 μM, respectively). In addition, M3'S proved to be a substrate of OATP1B1 and OATP2B1. These results suggest that MYR-containing dietary supplements may affect the OATP-mediated transport of certain drugs, and OATPs are involved in the tissue uptake of M3'S.
- MeSH
- cytochrom P-450 CYP3A metabolismus MeSH
- cytochrom P450 CYP2C9 metabolismus MeSH
- flavonoidy * farmakologie MeSH
- flavonoly farmakologie MeSH
- lidé MeSH
- polypeptid C přenášející organické anionty * metabolismus MeSH
- přenašeče organických aniontů * metabolismus MeSH
- sérový albumin metabolismus MeSH
- sírany metabolismus MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Lenvatinib is an orally effective tyrosine kinase inhibitor used to treat several types of tumors, including progressive, radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma. Although this drug is increasingly used in therapy, its metabolism and effects on the organism are still not described in detail. Using the rat as an experimental animal model, this study aimed to investigate the metabolism of lenvatinib by rat microsomal enzymes and cytochrome P450 (CYPs) enzymes recombinantly expressed in SupersomesTMin vitro and to assess the effect of lenvatinib on rat CYP expression in vivo. Two metabolites, O-desmethyl lenvatinib, and lenvatinib N-oxide, were produced by rat CYPs in vitro. CYP2A1 and 2C12 were found to be the most effective in forming O-desmethyl lenvatinib, while CYP3A2 was found to primarily form lenvatinib N-oxide. The administration of lenvatinib to rats caused changes in the expression of mRNA and protein, as well as the activity of various CYPs, particularly in an increase in CYP1A1. Thus, the administration of lenvatinib to rats has an impact on the level of CYPs.
- MeSH
- chinoliny * farmakologie MeSH
- fenylmočovinové sloučeniny * farmakologie MeSH
- inhibitory proteinkinas * farmakologie MeSH
- inhibitory tyrosinkinasy MeSH
- jaterní mikrozomy účinky léků MeSH
- játra * účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- messenger RNA metabolismus genetika MeSH
- oxidace-redukce * účinky léků MeSH
- potkani Sprague-Dawley MeSH
- systém (enzymů) cytochromů P-450 * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Polypragmazie, fenomén dnešní medicíny, přináší velké riziko vzniku lékových interakcí. Některé z nich mohou vést k závažným nežádoucím účinkům nebo selhání léčby, znalosti v této oblasti se dynamicky rozvíjejí. Farmakokinetické lékové interakce se mohou vyskytovat nejen při metabolizaci léčiv systémem izoenzymů cytochromu P450, ale i na úrovni transportérů, kterých je již popsána celá řada. Pro hodnocení jejich klinického významu je třeba se orientovat ve farmakodynamice a farmakokinetice léčiv, ale uvažovat i nad dalšími faktory, které dopad lékové interakce ovlivní. Lékař by měl znát běžně předepisovaná léčiva s vysokým interakčním potenciálem, mít povědomí o silných induktorech a inhibitorech CYP450 a také o možném vlivu genetického polymorfismu některých jeho izoforem. Neměl by se však spolehnout na interpretaci lékových interakcí pouze za využití dostupných interakčních databází. Žádný software zatím není schopen vyhodnocovat interakce komplexně a v kontextu konkrétního pacienta, jeho zdravotního stavu a komorbidit. Rovněž je třeba správně porozumět dostupným informacím a pozorováním z klinických studií a umět je převést do reálné praxe. S výhodou dnes již může lékař konzultovat problematiku lékových interakcí u konkrétního pacienta s klinickým farmaceutem nebo farmakologem. Tento článek shrnuje problematiku lékových interakcí, se zaměřením na ty méně intuitivní a s uvedením konkrétních příkladů z praxe.
Polypharmacy, a phenomenon of today’s medicine, brings a great risk of drug interactions. Some of them can lead to serious side effects or treatment failure, knowledge in this field is dramatically developing. Pharmacokinetic drug interactions can occur not only when drugs are metabolized by the cytochrome P450 isoenzyme system, but also at the level of transporters, a number of which have already been described. In order to assess their clinical significance, it is necessary to orient oneself in the pharmacodynamics and pharmacokinetics of drugs, but also to consider other factors that will influence the impact of drug interactions. The physician should be familiar with commonly prescribed drugs with a high interaction potential, be aware of strong inducers and inhibitors of CYP450, as well as the possible influence of genetic polymorphism of some of its isoforms. However, one should not rely on the interpretation of drug interactions only using available interaction databases. No software is yet capable of evaluating interactions comprehensively and in the context of a specific patient, their health status and comorbidities. Also, the information available from clinical studies and observations needs to be properly understood and translated into real practice. Nowadays, it is a great advantage a doctor can consult with a clinical pharmacist or pharmacologist on the issue of drug interactions in a specific patient. This article summarizes the issue of drug interactions, focusing on the less intuitive ones, with examples from practice.
- MeSH
- lékové interakce * MeSH
- lidé MeSH
- polypharmacy * MeSH
- systém (enzymů) cytochromů P-450 metabolismus účinky léků MeSH
- systémy cílené aplikace léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Luteolin and naringenin are flavonoids found in various foods/beverages and present in certain dietary supplements. After a high intake of these flavonoids, their sulfate and glucuronide conjugates reach micromolar concentrations in the bloodstream. Some pharmacokinetic interactions of luteolin and naringenin have been investigated in previous studies; however, only limited data are available in regard to their metabolites. In this study, we aimed to investigate the interactions of the sulfate and glucuronic acid conjugates of luteolin and naringenin with human serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Our main findings are as follows: (1) Sulfate conjugates formed more stable complexes with albumin than the parent flavonoids. (2) Luteolin and naringenin conjugates showed no or only weak inhibitory action on the CYP enzymes examined. (3) Certain conjugates of luteolin and naringenin are potent inhibitors of OATP1B1 and/or OATP2B1 enzymes. (4) Conjugated metabolites of luteolin and naringenin may play an important role in the pharmacokinetic interactions of these flavonoids.
- MeSH
- cytochrom P-450 CYP3A * metabolismus MeSH
- cytochrom P450 CYP2C19 metabolismus MeSH
- cytochrom P450 CYP2C9 metabolismus MeSH
- flavonoidy farmakologie MeSH
- glukuronidy MeSH
- lidé MeSH
- lidský sérový albumin metabolismus MeSH
- luteolin farmakologie MeSH
- přenašeče organických aniontů * metabolismus MeSH
- sírany metabolismus MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This study examined the biotransformation of phytocannabinoids in human hepatocytes. The susceptibility of the tested compounds to transformations in hepatocytes exhibited the following hierarchy: cannabinol (CBN) > cannabigerol (CBG) > cannabichromene (CBC) > cannabidiol (CBD). Biotransformation included hydroxylation, oxidation to a carboxylic acid, dehydrogenation, hydrogenation, dehydration, loss/shortening of alkyl, glucuronidation and sulfation. CBN was primarily metabolized by oxidation of a methyl to a carboxylic acid group, while CBD, CBG and CBC were preferentially metabolized by direct glucuronidation. The study also screened for the activity of recombinant human cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs), which could catalyze the hydroxylation and glucuronidation of the tested compounds, respectively. We found that CBD was hydroxylated mainly by CYPs 2C8, 2C19, 2D6; CBN by 1A2, 2C9, 2C19 and 2D6; and CBG by 2B6, 2C9, 2C19 and 2D6. CBC exhibited higher susceptibility to CYP-mediated transformation than the other tested compounds, mainly with CYPs 1A2, 2B6, 2C8, 2C19, 2D6 and 3A4 being involved. Further, CBD was primarily glucuronidated by UGTs 1A3, 1A7, 1A8, 1A9 and 2B7; CBN by 1A7, 1A8, 1A9 and 2B7; CBG by 1A3, 1A7, 1A8, 1A9, 2B4, 2B7 and 2B17; and the glucuronidation of CBC was catalyzed by UGTs 1A1, 1A8, 1A9 and 2B7.
- MeSH
- biotransformace MeSH
- glukuronosyltransferasa metabolismus MeSH
- jaterní mikrozomy * metabolismus MeSH
- kyseliny karboxylové MeSH
- lidé MeSH
- systém (enzymů) cytochromů P-450 * metabolismus MeSH
- uridindifosfát metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Alisertib (MLN8237), a novel Aurora A kinase inhibitor, is currently being clinically tested in late-phase trials for the therapy of various malignancies. In the present work, we describe alisertib's potential to perpetrate pharmacokinetic drug-drug interactions (DDIs) and/or to act as an antagonist of multidrug resistance (MDR). In accumulation assays, alisertib potently inhibited ABCC1 transporter, but not ABCB1 or ABCG2. The results of molecular modeling suggested a bifunctional mechanism for interaction on ABCC1. In addition, alisertib was characterized as a low- to moderate-affinity inhibitor of recombinant CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 isoenzymes, but without potential clinical relevance. Drug combination studies revealed the capability of alisertib to synergistically antagonize ABCC1-mediated resistance to daunorubicin. Although alisertib exhibited substrate characteristics toward ABCB1 transporter in monolayer transport assays, comparative proliferation studies showed lack of its MDR-victim behavior in cells overexpressing ABCB1 as well as ABCG2 and ABCC1. Lastly, alisertib did not affect the expression of ABCC1, ABCG2, ABCB1 transporters and CYP1A2, CYP3A4, CYP2B6 isozymes on mRNA level in various systemic and tumoral models. In conclusion, our study suggests that alisertib is a drug candidate with negligible potential for perpetrating systemic pharmacokinetic DDIs on ABCB1, ABCG2 and cytochromes P450. In addition, we introduce alisertib as an effective dual-activity chemosensitizer whose MDR-antagonistic capacities are not impaired by efflux or effect on MDR phenotype. Our in vitro findings provide important pieces of information for clinicians when introducing alisertib into the clinical area.
- MeSH
- ABC transportér z rodiny G, člen 2 genetika metabolismus MeSH
- azepiny farmakokinetika farmakologie MeSH
- buněčné linie MeSH
- katalytická doména MeSH
- konformace proteinů MeSH
- lékové interakce MeSH
- lidé MeSH
- molekulární modely MeSH
- P-glykoprotein genetika metabolismus MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům antagonisté a inhibitory MeSH
- psi MeSH
- pyrimidiny farmakokinetika farmakologie MeSH
- regulace genové exprese účinky léků MeSH
- simulace molekulového dockingu MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Lenvatinib, a small molecule tyrosine kinase inhibitor (TKI), exhibits good inhibitory effect in several types of carcinomas. Specifically, it is the most effective TKI used for treatment of thyroid cancer. To extend pharmacokinetics data on this anticancer agent, we aimed to identify the metabolites of lenvatinib formed during in vitro incubation of lenvatinib with human hepatic microsomes or recombinant cytochromes P450 (CYPs) by using high performance liquid chromatography and mass spectrometry. The role of CYPs in the oxidation of lenvatinib was initially investigated in hepatic microsomes using specific CYP inhibitors. CYP-catalytic activities in each microsomal sample were correlated with the amounts of lenvatinib metabolites formed by these samples. Further, human recombinant CYPs were employed in the metabolic studies. Based on our data, lenvatinib is metabolized to O-desmethyl lenvatinib, N-descyclopropyl lenvatinib and lenvatinib N-oxide. In the presence of cytochrome b5, recombinant CYP3A4 was the most efficient to form these metabolites. In addition, CYP1A1 significantly contributes to the lenvatinib metabolism. It was even more efficient in forming of O-desmethyl lenvatinib than CYP3A4 in the absence of cytochrome b5. The present study indicates that further research focused on drug-drug interactions, in particular on CYP3A4 and CYP1A1 modulators, is needed. This will pave new avenues towards TKIs-mediated personalized therapy.
- MeSH
- antitumorózní látky metabolismus MeSH
- chinoliny metabolismus MeSH
- fenylmočovinové sloučeniny metabolismus MeSH
- hmotnostní spektrometrie MeSH
- inhibitory cytochromu P450 farmakologie MeSH
- inhibitory proteinkinas metabolismus MeSH
- jaterní mikrozomy enzymologie metabolismus MeSH
- králíci MeSH
- krysa rodu rattus MeSH
- lékové interakce MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- oxidace-redukce MeSH
- potkani Wistar MeSH
- systém (enzymů) cytochromů P-450 účinky léků metabolismus MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Talazoparib (Talzenna) is a novel poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that is clinically used for the therapy of breast cancer. Furthermore, the drug has shown antitumor activity against different cancer types, including non-small cell lung cancer (NSCLC). In this work, we investigated the possible inhibitory interactions of talazoparib toward selected ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs) and evaluated its position in multidrug resistance (MDR). In accumulation studies, talazoparib interacted with the ABCC1 and ABCG2 transporters, but there were no significant effects on ABCB1. Furthermore, incubation assays revealed a negligible capacity of the tested drug to inhibit clinically relevant CYPs. In in vitro drug combination experiments, talazoparib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCC1 and ABCG2 expression, respectively. Importantly, the position of an effective MDR modulator was further confirmed in drug combinations performed in ex vivo NSCLC patients-derived explants, whereas the possible victim role was refuted in comparative proliferation experiments. In addition, talazoparib had no significant effects on the mRNA-level expressions of MDR-related ABC transporters in the MCF-7 cellular model. In summary, our study presents a comprehensive overview on the pharmacokinetic drug-drug interactions (DDI) profile of talazoparib. Moreover, we introduced talazoparib as an efficient MDR antagonist.
- MeSH
- ABC transportér z rodiny G, člen 2 genetika MeSH
- ABC transportéry genetika metabolismus MeSH
- lidé MeSH
- mnohočetná léková rezistence MeSH
- nádorové proteiny metabolismus MeSH
- nádory plic * MeSH
- nemalobuněčný karcinom plic * farmakoterapie genetika MeSH
- P-glykoproteiny genetika MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut-liver axis, however, butyrate may reach directly the liver and influence the drug-metabolizing ability of hepatic enzymes, and, indirectly, also the outcome of applied pharmacotherapy. The focus of our study was on the liver microsomal cytochrome P450 (CYP) 2A5, which is a mouse orthologue of human CYP2A6 responsible for metabolism of metronidazole, an antibiotic used to treat IBD. Our findings revealed that specific pathogen-free (SPF) and germ-free (GF) mice with dextran sulfate sodium (DSS)-induced colitis varied markedly in enzyme activity of CYP2A and responded differently to butyrate pre-treatment. A significant decrease (to 50%) of the CYP2A activity was observed in SPF mice with colitis; however, an administration of butyrate prior to DSS reversed this inhibition effect. This phenomenon was not observed in GF mice. The results highlight an important role of gut microbiota in the regulation of CYP2A under inflammatory conditions. Due to the role of CYP2A in metronidazole metabolism, this phenomenon may have an impact on the IBD therapy. Butyrate administration, hence, brings promising therapeutic potential for improving symptoms of gut inflammation; however, possible interactions with drug metabolism need to be further studied.
- MeSH
- antibakteriální látky škodlivé účinky farmakologie terapeutické užití MeSH
- antiflogistika farmakologie MeSH
- butyráty * farmakologie MeSH
- metronidazol farmakologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- síran dextranu škodlivé účinky MeSH
- střevní mikroflóra * MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- ulcerózní kolitida * chemicky indukované farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In today's modern society, it seems to be more and more challenging to cope with life stresses. The effect of psychological stress on emotional and physical health can be devastating, and increased stress is associated with increased rates of heart attack, hypertension, obesity, addiction, anxiety and depression. This review focuses on the possibility of an influence of psychological stress on the metabolism of selected antidepressants (TCAs, SSRIs, SNRIs, SARIs, NDRIs a MMAs) and anxiolytics (benzodiazepines and azapirone), as patients treated with antidepressants and/or anxiolytics can still suffer from psychological stress. Emphasis is placed on the drug metabolism mediated by the enzymes of Phase I, typically cytochromes P450 (CYPs), which are the major enzymes involved in drug metabolism, as the majority of psychoactive substances are metabolized by numerous CYPs (such as CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2A6, CYP2D6, CYP3A4). As the data on the effect of stress on human enzymes are extremely rare, modulation of the efficacy and even regulation of the biotransformation pathways of drugs by psychological stress can be expected to play a significant role, as there is increasing evidence that stress can alter drug metabolism, hence there is a risk of less effective drug metabolism and increased side effects.
