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

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

The genetic basis of variability in drug response is at the core of pharmacogenomics (PGx) studies, aiming at reducing adverse drug reaction (ADR), which have interethnic variability. This study used the Kardiovize Brno 2030 random urban Czech sample population to analyze polymorphisms in a wide spectrum of genes coding for liver enzymes involved in drug metabolism. We aimed at correlating real life drug consumption with pharmacogenomic profile, and at comparing these data with the SUPER-Finland Finnish PGx database. A total of 250 individuals representative of the Kardiovize Brno 2030 cohort were included in an observational study. Blood DNA was extracted and 59 single nucleotide polymorphisms within 13 genes (BCHE, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5, F2, F5, IFNL3, SLCO1B1, TPMT, UGT1A1, VKORC1), associated to different drug metabolizing rates, were characterized by genotyping using a genome wide commercial array. Widely used drugs such as anti-coagulant warfarin and lipid lowering agent atorvastatin were associated to an alarmingly high percentage of users with intermediate/poor metabolism for them. Significant differences in the frequency of normal/intermediate/poor/ultrarapid/rapid metabolizers were observed for CYPD26 (p<0.001), CYP2C19 (p<0.001) and UGT1A1 (p<0.001) between the Czech and the Finnish study populations. Our study demonstrated that administration of some popular drugs to a Czech random sample population is associated with different drug metabolizing rates and therefore exposing to risk for ADRs. We also highlight interethnic differentiation of some common pharmacogenetics variants between Central (Czech) and North European (Finnish) population studies, suggesting the utility of PGx-informed prescription based on variant genotyping.

• MeSH
• cytochrom P-450 CYP2D6 genetika   MeSH
• cytochrom P450 CYP2C19 genetika   metabolismus   MeSH
• cytochrom P450 CYP2C9 genetika   metabolismus   MeSH
• farmakogenetika * MeSH
• genotyp MeSH
• lidé MeSH
• polymorfismus genetický * MeSH
• polypeptid C přenášející organické anionty genetika   MeSH
• vitamin K - epoxid reduktázy genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

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• Klíčová slova
• studie EXPAND, siponimod,
• MeSH
• chronicko-progresivní roztroušená skleróza * diagnóza   farmakoterapie   MeSH
• cytochrom P450 CYP2C9 analýza   genetika   MeSH
• klinická studie jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• progrese nemoci MeSH
• receptory sfingosin-1-fosfátu antagonisté a inhibitory   terapeutické užití   MeSH
• roztroušená skleróza diagnóza   farmakoterapie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Silymarin is a mixture of flavonolignans isolated from the fruit of milk thistle (Silybum marianum (L.) Gaertner). Milk thistle extract is the active ingredient of several medications and dietary supplements to treat liver injury/diseases. After the oral administration, flavonolignans are extensively biotransformed, resulting in the formation of sulfate and/or glucuronide metabolites. Previous studies demonstrated that silymarin components form stable complexes with serum albumin and can inhibit certain cytochrome P450 (CYP) enzymes. Nevertheless, in most of these investigations, silybin was tested; while no or only limited information is available regarding other silymarin components and metabolites. In this study, the interactions of five silymarin components (silybin A, silybin B, isosilybin A, silychristin, and 2,3-dehydrosilychristin) and their sulfate metabolites were examined with human serum albumin and CYP (2C9, 2C19, 2D6, and 3A4) enzymes. Our results demonstrate that each compound tested forms stable complexes with albumin, and certain silymarin components/metabolites can inhibit CYP enzymes. Most of the sulfate conjugates were less potent inhibitors of CYP enzymes, but 2,3-dehydrosilychristin-19-O-sulfate showed the strongest inhibitory effect on CYP3A4. Based on these observations, the simultaneous administration of high dose silymarin with medications should be carefully considered, because milk thistle flavonolignans and/or their sulfate metabolites may interfere with drug therapy.

• MeSH
• cytochrom P-450 CYP2D6 metabolismus   MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• cytochrom P450 CYP2C19 metabolismus   MeSH
• cytochrom P450 CYP2C9 metabolismus   MeSH
• inhibitory enzymů chemie   metabolismus   farmakologie   MeSH
• lékové interakce fyziologie   MeSH
• lidé MeSH
• lidský sérový albumin metabolismus   MeSH
• silymarin chemie   metabolismus   farmakologie   MeSH
• sírany chemie   metabolismus   farmakologie   MeSH
• vazba proteinů fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Hereditary haemorrhagic telangiectasia (HHT) exhibits considerable phenotypic heterogeneity. Therefore, precise mutation screening and evaluation of patient risk must be determined in every HHT family. We present an HHT-2 case with an initial life-threatening bleeding episode that led to identification of a relatively large HHT family. Exome sequencing of the family members determined HHT-associated ACVRL1C1120T variant resulting in Arg374Trp substitution at the Ser/Thr-kinase domain region. The affected members display typical epistaxis symptomatology from early childhood resulting in sideropoenia. In addition, the HHT patients also displayed dermatology findings such as facial teleangiectasias and trunk/limb white spots representing post-inflammatory hypopigmentation. Interestingly, co-segregating with modifying cytochrome P450 (CYP2C) variant in the HHT patients led to NSAID intolerance marked by increased frequency of bleeding episodes. No arterial-venous malformation of the visceral organs and brain or association with cancer were observed. The heterogeneity of clinical presentation and the role of other variants support the need of regular patient monitoring and development of a nation-wide patient registry.

• MeSH
• cytochrom P450 CYP2C9 genetika   MeSH
• epistaxe MeSH
• hereditární hemoragická teleangiektazie genetika   MeSH
• lidé MeSH
• nádory kůže genetika   MeSH
• registrace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Warfarin v příštím roce oslaví své 65. výročí. Ačkoliv byla v posledních letech na trh uvedena řada nových perorálních antikoagulancií, stále zůstává jedním z nejpoužívanějších léčiv. Dle odhadů jej v celosvětovém měřítku užívá 0,5−1,5 % celosvětové populace. Od konce sedmdesátých let je znám i mechanismus jeho účinku, tj. inhibice epoxid reduktázy a s tím související nedostatečná syntéza koagulačních faktorů závislých na vitaminu K. Zásadní komplikací terapie je významná variabilita dávkování a úzké terapeutické rozmezí. Ustálených hodnot INR je dosaženo při dávkování 1−20 mg za den, ale i v širším rozmezí. Dosažení cílové hodnoty INR může trvat několik týdnů až měsíců. Během tohoto období jsou pacienti vystaveni zvýšenému riziku nedostatečné, nebo naopak nadměrné antikoagulace. Komplikace vyplývající z nesprávného dávkování warfarinu a z následné nutnosti vyhledání lékařské péče patří stále k nejčastěji hlášeným nežádoucím příhodám. Warfarin tedy zůstává v centru pozornosti vědeckých skupin i po půlstoletí. Kromě dnes již známých negenetických faktorů (BMI, hmotnost, pohlaví, věk, dieta a současně užívaná léčiva) jsou v poslední době podrobně zkoumány faktory genetické (především polymorfismy CYP2C9 a VKORC1) a jejich klinické využití ve vztahu k predikci správné dávky warfarinu.

Warfarin will celebrate its 65th “birthday” next year. Although many new oral anticoagulants have been launched during the last years, it remains one of the most popular medications. It has been estimated that between 0.5% and 1.5% of the world population take warfarin. The mechanism of its action, i.e. inhibition of epoxide reductase leading to reduced synthesis of vitamin K‑dependent coagulation factors, has been known since the end of the 1970th. Significant variability of its dosing and narrow therapeutic window are the crucial complications of warfarin use. Steady INR values are being achieved with 1mg to 20mg of warfarin daily; the range of dosages can be even wider. Moreover, steady INR values may not be reached before several weeks to months of therapy have elapsed. During this period, the patients are at risk of insufficient or too intense anticoagulation. Complications following incorrect warfarin dosing and ensuing need of medical attention still represent the most common adverse events. Warfarin thus never stopped, event after half of a century, to attract the interest of scientific groups. Beside the well‑known non‑genetic factors (BMI, weight, sex, age, diet, and concomitant medications), genetic factors influencing warfarin therapy have been studied meticulously in the past years (especially CYP2C9 a VKORC1 polymorphisms); special attention has been paid to their clinical use with respect to correct warfarin dose prediction.

• MeSH
• algoritmy MeSH
• cytochrom P450 CYP2C9 účinky léků   MeSH
• etnologie MeSH
• farmakogenetika * MeSH
• lidé MeSH
• polymorfismus genetický genetika   účinky léků   MeSH
• rasové skupiny genetika   MeSH
• vitamin K - epoxid reduktázy účinky léků   MeSH
• výpočet dávky léku MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• warfarin * aplikace a dávkování   farmakokinetika   MeSH
• značení léčiv MeSH
• Check Tag
• lidé MeSH

CYP2C and CYP2 J enzymes, commonly named as cytochrome P450 (CYP) epoxygenases, convert arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs), biologically active eicosanoids with many functions in organism. EETs are rapidly hydrolysed to less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). We investigated spatio-temporal expression pattern of CYP2C8, CYP2C9, CYP2 J2 and sEH in normal human placenta by immunohistochemical method. In the villous trophoblast, CYP2C8 was the most abundant protein. Its expression is higher than the CYP2C9 and CYP2 J2 in the cytotrophoblast in the embryonic stage of development and remains higher in syncytiotrophoblast of term placenta. Unlike to CYP2C8, CYP2C9 and CYP2 J2 expression decrease in term placenta. sEH expression increases with gestation age and is strictly limited to cytotrophoblast in embryonic and foetal stages of the development. Moreover, CYP2C8 shows more intensive staining than the other protein monitored in Hofbauer cells in villous stroma. Specific information regarding the exact role of EETs and DHETs functions in a normal placenta is still unknown. Based on CYP epoxygenases and sEH localization and well known information about the functions of placental structures during development, we suggest that these enzymes could play different roles in various cell populations in the placenta. As the placenta is absolutely crucial for prenatal development, arachidonic acid is essential part of human nutrient and CYP epoxygenases expression can be affected by xenobiotics, further investigation of the exact role of CYP epoxygenases, sEH, and their metabolites in normal pregnancy and under pathological conditions is needed.

• MeSH
• cytochrom P450 CYP2C8 biosyntéza   MeSH
• cytochrom P450 CYP2C9 biosyntéza   MeSH
• lidé MeSH
• placenta cytologie   enzymologie   MeSH
• regulace genové exprese enzymů fyziologie   MeSH
• systém (enzymů) cytochromů P-450 biosyntéza   MeSH
• těhotenské proteiny biosyntéza   MeSH
• těhotenství metabolismus   MeSH
• Check Tag
• lidé MeSH
• těhotenství metabolismus   MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective.

• MeSH
• antikoagulancia aplikace a dávkování   farmakokinetika   MeSH
• cytochrom P450 CYP2C9 genetika   MeSH
• etnicita genetika   MeSH
• farmakogenetika * MeSH
• genetické markery * MeSH
• lidé MeSH
• shluková analýza MeSH
• vitamin K - epoxid reduktázy genetika   MeSH
• warfarin aplikace a dávkování   farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied. Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver microsomal CYP3A4 down to 42% (at rocuronium concentration 189 μM) was found. This effect has been confirmed with two CYP3A4 substrates, testosterone (formation of 6β-hydroxytestosterone) and diazepam (temazepam formation). CYP2C9 and CYP2C19 activities were inhibited down to 75-80% (at the same rocuronium concentration). Activities of other microsomal CYPs have not been inhibited by rocuronium. To prove the possibility of rocuronium interaction with other drugs (diazepam), the effect of rocuronium on formation of main diazepam metabolites, temazepam (by CYP3A4) and desmethyldiazepam, (also known as nordiazepam; formed by CYP2C19) in primary culture of human hepatocytes has been examined. Rocuronium has caused inhibition of both reactions by 20 and 15%, respectively. The results open a possibility that interactions of rocuronium with drugs metabolized by CYP3A4 (and possibly also CYP2C19) may be observed.

• MeSH
• androstanoly metabolismus   farmakologie   MeSH
• cytochrom P-450 CYP3A metabolismus   fyziologie   MeSH
• cytochrom P450 CYP2C19 metabolismus   fyziologie   MeSH
• cytochrom P450 CYP2C9 metabolismus   MeSH
• cytochromy metabolismus   MeSH
• diazepam farmakologie   MeSH
• hepatocyty metabolismus   MeSH
• inhibitory cytochromu P450 MeSH
• jaterní mikrozomy enzymologie   MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé MeSH
• nervosvalové látky nedepolarizující farmakologie   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• vazebná místa MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH