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

Tapinarof (3,5-dihydroxy-4-isopropylstilbene) is a therapeutic agent used in the treatment of psoriasis (VTAMA®). In this study, we examined the redox behaviour, (photo)stability, (photo)toxicity and (bio)transformation of tapinarof in the context of a structure-activity relationship study. Selected derivatives of the structurally related tapinarof were investigated, namely resveratrol, pterostilbene, pinosylvin and its methyl ether. Tapinarof undergoes electrochemical oxidation in a neutral aqueous medium at a potential of around +0.5 V (vs. Ag|AgCl|3M KCl). The anodic reaction of this substance is a proton-dependent irreversible and adsorption-driven process. The pKa value of tapinarof corresponds to 9.19 or 9.93, based on empirical and QM calculation approach, respectively. The oxidation potentials of tapinarof and its analogues correlate well with their HOMO (highest occupied molecular orbital) energy level. The ability to scavenge the DPPH radical decreased in the order trolox ≥ resveratrol > pterostilbene > tapinarof > pinosylvin ≫ pinosylvin methyl ether. It was also confirmed that tapinarof, being a moderate electron donor, is able to scavenge the ABTS radical and inhibit lipid peroxidation. The 4'-OH group plays a pivotal role in antioxidant action of stilbenols. During the stability studies, it was shown that tapinarof is subject to spontaneous degradation under aqueous conditions, and its degradation is accelerated at elevated temperatures and after exposure to UVA (315-399 nm) radiation. In aqueous media at pH 7.4, we observed an ∼50 % degradation of tapinarof after 48 h at laboratory temperature. The main UVA photodegradation processes include dihydroxylation and hydration. In conclusion, the phototoxic effect of tapinarof on a human keratinocytes cell line (HaCaT) was evaluated. Tapinarof exhibited a clear phototoxic effect, similar to phototoxic standard chlorpromazine. The IC50 values of the cytotoxicity and phototoxic effects of tapinarof correspond to 27.6 and 3.7 μM, respectively. The main HaCaT biotransformation products of tapinarof are sulfates and glucuronides.

• MeSH
• antioxidancia farmakologie   chemie   MeSH
• buněčné linie keratinocytů HaCaT MeSH
• fototoxická dermatitida MeSH
• keratinocyty * účinky léků   metabolismus   účinky záření   MeSH
• kůže účinky léků   metabolismus   účinky záření   patologie   MeSH
• lidé MeSH
• oxidace-redukce * MeSH
• resveratrol farmakologie   analogy a deriváty   chemie   MeSH
• stilbeny * farmakologie   chemie   MeSH
• ultrafialové záření MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

We report the forensic case of a 42-year-old man, a known drug user, who died at home and whose body was only discovered 2 months later. Autopsy was performed on a corpse in the late postmortem stage where no apparent cause of death was found. A toxicological screening of biological materials (blood, urine and gastric content) using liquid chromatography with different types of mass detection (ion trap and high-resolution) revealed the presence of methoxetamine (MXE), a ketamine analog, and its metabolites. MXE and a number of its metabolites (e.g., O-desmethyl, N-desethyl, hydroxy, glucuronides and sulfates) were identified in urine. Based on the results, a method using liquid chromatography with tandem mass spectrometry was developed and validated for the determination of MXE concentration in biological materials. The following values of MXE concentration were found: blood-3.6 ng/mL, urine-70.5 ng/mL and gastric content-18.0 ng/mL. Given the absence of other drugs, medications and poisons, it can be inferred that despite relatively low blood concentrations, MXE contributed to the victim's death. The present case demonstrates that even after 2 months, MXE and its several metabolites can be detected and determined in the human cadaver at a relatively advanced stage of decomposition.

• MeSH
• cyklohexanony * analýza   metabolismus   MeSH
• cyklohexylaminy * MeSH
• dospělí MeSH
• lidé MeSH
• mrtvola MeSH
• pitva MeSH
• tělesné tekutiny * metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky 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

Vericigvát je nový lék pro léčbu chronického srdečního selhání. Účinkuje jako přímý stimulátor solubilní guanylátcyklázy, jehož aktivita není závislá na přítomnosti NO. Je podáván perorálně jedenkrát denně v dávce 2,5, 5 a 10 mg s postupnou titrací nahoru. Je metabolizován jaterními glukuronidázami UGT1A9 a 1A1 na neaktivní N-glukuronid. Přibližně 53 % podané dávky je vyloučeno močí, zatímco 45 % stolicí. Biologický poločas eliminace u zdravých dobrovolníků byl průměrně 20 hodin, u nemocných se srdečním selháním průměrně 30 hodin. Jeho nejčastějším nežádoucím účinkem s incidencí kolem 16 % je hypotenze. Vyznačuje se minimálním potenciálem lékových interakcí.

Vericiguat is a new drug for the treatment of chronic heart failure. It acts as a direct sGS stimulator whose activity is not dependent on the presence of NO. It is administered orally once daily at doses of 2.5, 5 and 10 mg with gradual upward titration. It is metabolized by hepatic glucuronidases UGT1A9 and 1A1 to inactive N-glucuronide. Approximately 53 % of the administered dose is excreted in the urine, while 45% in the faeces. The biological elimination half-life in healthy volunteers averaged 20 hours and in patients with heart failure averaged 30 hours. Its most common adverse effect with an incidence of about 16% is hypotension. It has minimal potential for drug interactions.

• Klíčová slova
• vericigvát,
• MeSH
• heterocyklické sloučeniny bicyklické farmakokinetika   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• hypotenze chemicky indukované   MeSH
• lékové interakce MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• pyrimidiny farmakokinetika   farmakologie   škodlivé účinky   terapeutické užití   MeSH
• srdeční selhání * farmakoterapie   MeSH
• Check Tag
• lidé MeSH

While there are hundreds of synthetic steroids conjugates with acids, sugars, proteins and other molecules, only two types of conjugates occur in living organisms, namely sulfates and glucuronides. Steroid glucuronidation in the human liver is the main mechanism controlling the levels and biological activity of unconjugated hormones, and glucuronides are their main excretion products. This process is generally irreversible. On the other hand, sulfates possess their own biological activity that differs from that of the unconjugated steroid, emphasizing the importance of steroid sulfatases and sulfotransferases. Due to their negative charge, steroid sulfates cannot cross the blood-cell barrier and have to use transporters. Their efflux is mediated by specific transporters of the ATP binding cassette protein group, which thus are further factors controlling their physiological effects. Steroid sulfates, especially dehydroepiandrosterone sulfate (DHEAS) are neuroactive steroids, with well-known effects as allosteric modulators of some neurotransmitter receptors, functioning as ion channels, such as gamma-aminobutyric acid, type A (GABAA) receptors or N-methyl-D-aspartate (NMDA) receptors. In this minireview, we highlight some recent findings of non-genomic steroid sulfate actions through specific G-protein coupled receptors (GPCR), which we believe show the way of further research. A few studies have even indicated that sulfates such as DHEAS may even indirectly regulate gene expression via ligand binding to the membrane receptor and, through G-protein and second messenger formation, activate proteins like cAMP Regulated Elements Binding protein (CREB), which then binds to regulated DNA elements of the expressed gene, in a "classical" genomic effect.

• MeSH
• biologický transport MeSH
• fosforylace MeSH
• lidé MeSH
• signální transdukce * MeSH
• sírany * metabolismus   MeSH
• steroidy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Pochopení cest metabolizace inhibitorů SGLT2 (gliflozinů) je jednou z podmínek bezpečné terapie těmito léčivy. Glifloziny se v organismu metabolizují prakticky jen glukuronidací, což je velmi neobvyklé a lékaři i farmaceuti s tím musejí počítat. Největší část všech gliflozinů se metabolizuje cestou UGT1A9, v případě dapagliflozinu je tato cesta rozhodující, naopak empagliflozin je metabolizován hned čtyřmi izoenzymy UGT, což se projevuje zanedbatelným vlivem jejich polymorfismů a lékových interakcí. Glukuronidy vzniklé metabolizací gliflozinů jsou dobře rozpustné ve vodě, a jsou proto eliminovány ledvinami aktivním transportem. Míra glukuronidace jednotlivých gliflozinů je různá, nejnižší je v případě empagliflozinu a nejvyšší u dapagliflozinu.

Understanding the metabolism pathways of SGLT2 inhibitors (gliflozins) is one of the conditions for safe therapy with these drugs. Gliflozins are metabolized in the body practically only by glucuronidation, which is very unusual. Both doctors and pharmacists must count it in. Most gliflozins are metabolized by UGT1A9. In the case of dapagliflozin, this is the decisive pathway, whereas empagliflozin is metabolized by four UGT isoenzymes, which manifests as a negligible effect of their polymorphisms and drug interactions. Glucuronides formed by the metabolism of gliflozins are readily soluble in water and are therefore eliminated by active renal transport. The degree of glucuronidation of individual gliflozins is different; the lowest is in the case of empagliflozin and the highest in the case of dapagliflozin.

• MeSH
• biotransformace fyziologie   MeSH
• farmakokinetika MeSH
• glifloziny aplikace a dávkování   farmakokinetika   MeSH
• glukuronidy metabolismus   MeSH
• glukuronosyltransferasa genetika   MeSH
• lidé MeSH
• transportér 2 pro sodík a glukózu * MeSH
• Check Tag
• lidé MeSH

Inhibitory SGLT2 (glifloziny) se v organismu metabolizují prakticky jen glukuronidací a jen minimálně oxidativní cestou. Současně jsou některé glifloziny substráty transportních systémů P‐glykoproteinu, BCRP a MRP‐2. Z těchto vlastností gliflozinů se odvozují jejich farmakokinetické lékové interakce. Z mechanismu účinku gliflozinů vyplývá, že zvyšují exkreci glukózy a natria močí, čímž zvyšují také exkreci vody. Kombinace gliflozinů s diuretiky působí synergicky na natriurézu a může vyvolat hypotenzi a dehydrataci. Kombinace gliflozinů s inzulinem nebo inzulinovými sekretagogy pak může zvýšit riziko vzniku hypoglykemických příhod. Glifloziny naproti tomu prakticky neovlivňují osud jiných léků v organismu a mají jen omezené množství klinicky relevantních lékových interakcí. Ke klinicky nejvýznamnějším patří indukce glukuronidace gliflozinů, synergický efekt při souběžném podávání diuretik a vliv gliflozinů na exkreci solí lithia.

SGLT2 inhibitors (gliflozins) are metabolized in the body practically mainly by glucuronidation and only minimally by the oxidative route. At the same time, some gliflozins are substrates of the P‐glycoprotein, BCRP and MRP‐2 transport systems. These properties of gliflozins indicate their pharmacokinetic drug interactions. The mechanism of action of gliflozins suggests that they increase glucose and sodium excretion in the urine, thereby also increasing water excretion. The combination of gliflozins with diuretics acts synergistically on sodium excretion and may cause hypotension and dehydration. Combining gliflozins with insulin or secretagogues may increase the risk of hypoglycemic episodes. Gliflozins, on the other hand, have virtually no effect on the fate of other drugs. Gliflozins have only a limited number of clinically relevant drug interactions, the most clinically important being the induction of gliflozin glucuronidation, the synergistic effect of co‐administered diuretics and the effect of gliflozins on lithium salt excretion.

• MeSH
• akutní poškození ledvin etiologie   MeSH
• diuretika aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• glifloziny * aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• glukuronosyltransferasa antagonisté a inhibitory   MeSH
• hypoglykemie etiologie   MeSH
• hypotenze etiologie   MeSH
• inzulin aplikace a dávkování   terapeutické užití   MeSH
• kyselina niflumová aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kyselina valproová aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lékové interakce MeSH
• lidé MeSH
• lithium aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Glifloziny jsou antidiabetika se specifickým metabolismem, který je založen zejména na jejich glukuronizaci. Vzniklé glukuronidy jsou eliminovány především močí, zatímco nemetabolizovaná část gliflozinů se eliminuje převážně žlučí. Nejvýznamnější glukuronosyltransferázou při metabolismu gliflozinů je UGT1A9. Transport gliflozinů se děje zejména cestou efluxních transportních systémů P glykoproteinu, BCRP a MRP2. V metabolismu a transportu gliflozinů jsou poměrně značné rozdíly, z nichž se odvíjejí odlišnosti v potřebě redukce dávek gliflozinů při porušené funkci ledvin nebo jater.

Gliflozins are antidiabetics with a specific metabolism based mainly on their glucuronidation. The resulting glucuronides are eliminated primarily in the urine, while the unmetabolised part of gliflozins is eliminated mainly in bile. The most important glucuronosyltransferase in gliflozin metabolism is UGT1A9. Gliflozins are principally transported via the efflux transport systems P-glycoprotein, BCRP and MRP-2. There are relatively significant differences in gliflozin metabolism and transport, resulting in differences in the need for dose reduction for renal or hepatic impairment.

• MeSH
• glifloziny * farmakokinetika   metabolismus   MeSH
• lidé MeSH
• transportér 2 pro sodík a glukózu farmakokinetika   metabolismus   MeSH
• transportní proteiny pro sodík a glukosu * farmakokinetika   metabolismus   MeSH
• Check Tag
• lidé MeSH