AIMS: Liver cytochromes (CYPs) play an important role in drug metabolism but display a large interindividual variability resulting both from genetic and environmental factors. Most drug dose adjustment guidelines are based on genetics performed in healthy volunteers. However, hospitalized patients are not only more likely to be the target of new prescriptions and drug treatment modifications than healthy volunteers, but will also be more subject to polypharmacy, drug-drug interactions, or to suffer from disease or inflammation affecting CYP activities. METHODS: We compared predicted phenotype based on genetic data and measured phenotype using the Geneva cocktail to determine the extent of drug metabolizing enzyme variability in a large population of hospitalized patients (>500) and healthy young volunteers (>300). We aimed to assess the correlation between predicted and measured phenotype in the two populations. RESULTS: We found that, even in cases where the genetically predicted metabolizer group correlates well with measured CYP activity at group level, this prediction lacks accuracy for the determination of individual metabolizer capacities. Drugs can have a profound impact on CYP activity, but even after combining genetic and drug treatment information, the activity of a significant proportion of extreme metabolizers could not be explained. CONCLUSIONS: Our results support the use of measured metabolic ratios in addition to genotyping for accurate determination of individual metabolic capacities to guide personalized drug prescription.

• MeSH
• dospělí MeSH
• fenotyp MeSH
• genotyp MeSH
• hospitalizace MeSH
• léčivé přípravky metabolismus   MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři MeSH
• systém (enzymů) cytochromů P-450 * genetika   metabolismus   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

AIM: Despite the high sensitivity of neonatal screening in detecting the classical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, one of the unclear issues is identifying asymptomatic children with late onset forms. The aim of this nationwide study was to analyse the association between genotype and screened level of 17-hydroxyprogesterone in patients with the late onset form of 21-hydroxylase deficiency and to quantify false negativity. METHODS: In the Czech Republic, 1,866,129 neonates were screened (2006-2022). Among this cohort, 159 patients were confirmed to suffer from 21-hydroxylase deficiency, employing the 17-hydroxyprogesterone birthweight/gestational age-adjusted cut-off limits, and followed by the genetic confirmation. The screening prevalence was 1:11,737. Another 57 patients who were false negative in neonatal screening were added to this cohort based on later diagnosis by clinical suspicion. To our knowledge, such a huge nationwide cohort of false negative patients has not been documented before. RESULTS: Overall, 57 patients escaped from neonatal screening in the monitored period. All false negative patients had milder forms. Only one patient had simple virilising form and 56 patients had the late onset form. The probability of false negativity in the late onset form was 76.7%. The difference in 17-hydroxyprogesterone screening values was statistically significant (p<0.001) between severe forms (median 478.8 nmol/L) and milder (36.2 nmol/L) forms. Interestingly, the higher proportion of females with milder forms was statistically significant compared with the general population. CONCLUSIONS: A negative neonatal screening result does not exclude milder forms of 21-hydroxylase deficiency during the differential diagnostic procedure of children with precocious pseudopuberty.

• MeSH
• 17-alfa-hydroxyprogesteron * krev   MeSH
• falešně negativní reakce MeSH
• kongenitální adrenální hyperplazie * diagnóza   krev   MeSH
• lidé MeSH
• novorozenec MeSH
• novorozenecký screening * metody   MeSH
• steroid-21-hydroxylasa genetika   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Vysokoškolská učebnice, která se zaměřuje na farmakokinetiku, konkrétně na metabolismus xenobiotik a léčiv.

• MeSH
• enzymy MeSH
• farmakokinetika MeSH
• farmakologie MeSH
• xenobiotika MeSH

• Konspekt
• Farmacie. Farmakologie
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• farmacie a farmakologie
• NLK Publikační typ
• učebnice vysokých škol

Recent advances in avian melanogenesis have pinpointed multiple genetic loci associated with color polymorphisms, predominantly in the plumage of chickens, quails, and pigeons. However, the genetic basis of melaninization in parrot plumage remains elusive. Previously, we showed that mutations in the melanosomal ion-transporter SLC45A2 lead to a complete loss of blue structural color in green parrot feathers, leaving only yellow psittacofulvin. Yet, several color morphs involving partial or complete melanin reduction are common in captive-bred parrots that have not been studied. To bridge this gap, we investigated two new color morphs of parrot plumage: non-sex-linked recessive lutino (NSL), which entirely inhibits blue structural coloration, and the sex-linked recessive cinnamon, which reduces the intensity of blue structural coloration. Our genotypic analysis revealed that tyrosinase (TYR) variants are responsible for the NSL phenotype in Fischer's lovebird and green-cheeked parakeet, while tyrosinase related protein 1 (TYRP1) variants are associated with the cinnamon phenotype in the rose-ringed parakeet. When transfected into HEK293T cells, the candidate substitutions significantly affected tyrosinase enzymatic activity. This study underscores tyrosinase and related enzymes' role in parrot feather coloration, enhancing our understanding of avian melanogenesis as well as the conserved functions of melanogenic components across different species.

• MeSH
• fenotyp MeSH
• lidé MeSH
• melaniny metabolismus   MeSH
• oxidoreduktasy * metabolismus   genetika   MeSH
• papouškovití * genetika   metabolismus   MeSH
• peří * enzymologie   metabolismus   MeSH
• pigmentace * genetika   MeSH
• ptačí proteiny * metabolismus   genetika   MeSH
• tyrosinasa * metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Článek má za cíl seznámit čtenáře s problematikou farmakogenetického (PGx) vyšetření v oboru psychiatrie, které dnes představuje dostupný a významný nástroj personalizované medicíny. PGx testování umožňuje upravit farmakoterapii na základě genetických predispozic pacientů. V rámci oboru psychiatrie se zaměřuje zejména na polymorfismy v genech odpovědných za metabolismus léčiv, především enzymy cytochromu P450, jako jsou CYP2C19 a CYP2D6. Toto vyšetření může v praxi pomoci predikovat účinnost nebo toxicitu léčiv, a tím zlepšit bezpečnost a efektivitu farmakoterapie. Ve studii realizované v Psychiatrické nemocnici Bohnice byli testováni pacienti, kteří vykazovali známky farmakorezistence, odlišnost ve výsledcích vyšetření monitorování plazmatických hladin (TDM) nebo např. výrazné nežádoucí účinky při terapii běžnými dávkami. Až 75 % testovaných pacientů mělo změněnou funkci jednoho nebo obou testovaných izoenzymů CYP, tedy fenotyp pomalého, ultrarychlého, rychlého nebo intermediárního metabolizéra. Interpretace výsledků PGx vyšetření je klíčová a měla by být prováděna odborníkem, který má zkušenosti v této oblasti, hluboké znalosti farmakokinetiky a také veškeré potřebné informace o konkrétním pacientovi. Pouze v takovém případě může PGx vyšetření významně ovlivnit správný výběr a dávkování psychofarmak, jejichž účinnost závisí na fenotypu pacientů (zejm. risperidon, haloperidol, venlafaxin, tricyklická antidepresiva, es-/citalopram aj.). Správná interpretace výsledků také umožňuje optimalizaci medikace. To přispívá k minimalizaci rizika vzniku vedlejších účinků a zajištění lepších výstupů léčby. Na závěr je uvedena jedna kazuistika reflektující reálnou situaci, kdy PGx vyšetření sehrálo důležitou roli při rozhodování o výběru farmakoterapie.

Our article aims to introduce the reader to pharmacogenetic (PGx) testing in psychiatry, where it currently represents an available and significant tool in personalized medicine. PGx testing enables the adjustment of pharmacotherapy based on patients' genetic predispositions. In psychiatry, PGx testing focuses on polymorphisms in genes responsible for drug metabolism, primarily cytochrome P450 enzymes such as CYP2C19 and CYP2D6. In clinical practice, these tests can help predict drug efficacy or toxicity, thereby improving the safety and effectiveness of pharmacotherapy. PGx testing, which was conducted at the Bohnice Psychiatric Hospital, was done on patients who exhibited signs of drug resistance, discrepancies in therapeutic drug monitoring (TDM), or significant adverse effects during therapy with standard doses. Results showed that up to 75% of the tested patients had altered function of one or both CYP isoenzymes (i. e., slow, ultra-rapid, rapid, or intermediate metabolizer phenotypes). The interpretation of PGx test results is crucial and should be performed by professionals with expertise in this field. Additionally, a thorough understanding of pharmacokinetics, as well as comprehensive patient-specific information, is required. Only under these conditions can PGx testing significantly influence the correct selection and optimal dosing of psychotropic drugs, especially those whose effectiveness depends on the patient's phenotype (e.g., risperidone, haloperidol, venlafaxine, tricyclic antidepressants, es-/citalopram, etc.). Correct interpretation of PGx results also enables medication optimization, contributing to individualized therapy. This minimizes the risk of side effects and ensures better treatment outcomes. Our article concludes with a case report illustrating a real-life situation in which PGx testing played a key role in guiding pharmacotherapy decisions.

• MeSH
• cytochrom P-450 CYP2D6 genetika   metabolismus   MeSH
• cytochrom P450 CYP2C19 genetika   metabolismus   MeSH
• farmakogenetika * MeSH
• lidé středního věku MeSH
• lidé MeSH
• paranoidní schizofrenie farmakoterapie   patologie   MeSH
• pilotní projekty MeSH
• polymorfismus genetický MeSH
• poruchy spojené s užíváním amfetaminu farmakoterapie   MeSH
• psychotropní léky * aplikace a dávkování   metabolismus   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• přehledy MeSH

BACKGROUND: Low levels of vitamin D have been associated with several autoimmune diseases. A growing body of evidence supports the association of vitamin D with skeletal muscle damage, regeneration, and energy and lipid metabolism. The aim was to analyse vitamin D and its receptor (VDR) in the muscle tissue of patients with idiopathic inflammatory myopathies (IIM) and to relate them to clinical parameters and muscle lipid and energy metabolism. METHODS: Forty-six patients with IIM and 67 healthy controls (HC) were included in the study. 27 IIM patients participated in a 24-week exercise intervention. Muscle biopsies were obtained from 7 IIM patients before/after training, 13 non-exercising IIM controls, and 21 HC. Circulating concentrations of 25(OH)D and 1,25(OH)D were measured. Gene expression of VDR and CYP27B1, the enzyme converting 25(OH)D to hormonally active 1,25(OH)D, was determined by qPCR in muscle tissue and primary muscle cells. Lipid oxidative metabolism was assessed in muscle tissue (mRNA, qPCR) and primary muscle cells (radioactive assays). RESULTS: Lower levels of active 1,25(OH)D were observed in IIM patients compared with HC (mean ± SD: 125.0 ± 45.4 vs. 164.7 ± 49.2 pmol/L; p < 0.0001). 25(OH)D was associated with CRP (r = -0.316, p = 0.037), MITAX (r = -0.311, p = 0.040) and HAQ (r = -0.390, p = 0.009) in IIM. After 24 weeks of training, active 1,25(OH)D was associated with MMT8 (r = 0.866, p < 0.0001), FI-2 (r = 0.608, p = 0.013) and HAQ (r = -0.537, p = 0.032). Gene expression of both VDR and CYP27B1 in primary muscle cells decreased after training (p = 0.031 and p = 0.078, respectively). Associations of VDR mRNA in muscle tissue with MMT-8 (IIM: r = -0.559, p = 0.013), serum CK (HC: r = 0.484, p = 0.031), myoglobin (IIM: r = 0.510, p = 0.026) and myostatin (IIM: r = -0.519, p = 0.023) were observed. The expression of VDR in differentiated muscle cells correlated negatively with the complete oxidation of palmitic acid (r = -0.532, p = 0.028). Muscle mRNA of carnitine palmitoyl transferase 1 (CPT1) (downregulated in IIM, p = 0.001) correlated positively with serum 1,25(OH) vitamin D (r = 0.410, p = 0.042). CONCLUSION: Reduced biologically active vitamin D in circulation suggests its impaired metabolism in IIM. Serum vitamin D levels and gene expression of its receptor and activating enzyme in muscle tissue were modified by regular exercise and associated with disease manifestations, physical fitness, and muscle lipid metabolism of IIM patients.

• MeSH
• 1-alfa-hydroxylasa 25-hydroxyvitaminu D3 metabolismus   MeSH
• dospělí MeSH
• kosterní svaly * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolismus lipidů * fyziologie   MeSH
• myozitida * metabolismus   MeSH
• receptory kalcitriolu * metabolismus   MeSH
• senioři MeSH
• tělesná výkonnost * fyziologie   MeSH
• vitamin D * krev   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Chronic Kidney Disease (CKD) is associated with heightened risk of thrombosis. Prescription of anticoagulants is key to manage it; however, CKD patients have shown an increased risk of bleeding under anticoagulation therapy compared to non-CKD patients. We hypothesized that the sex could modify the metabolism of indoxyl sulfate (IS), a uremic toxin and Apixaban. Our intoxication model shows that higher doses of IS and apixaban accumulate in the plasma of female mice because of expression differences in efflux transporters and cytochromes in the liver, ileum and kidneys, when compared to males. Furthermore, we found that accumulation of apixaban in females contributes to increased bleeding. Transcriptional analysis of liver samples revealed elevated Sult1a1 but reduced Abcg2 and Cyp3a11 in female mice, while in the kidneys the expression rates of Oat1 and Oat3 were respectively lower and higher than those observed in males, potentially affecting drug clearance. Whole proteomics liver analysis confirmed the previous transcriptional results at the protein level and revealed that sex had a major influence in regulating both coagulation and drug metabolism pathways. Thus, our findings underline the need for inclusive clinical and preclinical trials to accurately reflect sex-specific metabolic variations, and to consider CKD-specific changes to optimize dosing, minimize side effects, and improve patient outcomes.

• MeSH
• ABC transportér z rodiny G, člen 2 metabolismus   genetika   MeSH
• antikoagulancia aplikace a dávkování   metabolismus   MeSH
• chronická renální insuficience metabolismus   farmakoterapie   MeSH
• cytochrom P-450 CYP3A metabolismus   genetika   MeSH
• indican * metabolismus   krev   MeSH
• játra * metabolismus   účinky léků   MeSH
• krvácení metabolismus   MeSH
• ledviny metabolismus   účinky léků   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• přenašeče organických aniontů nezávislé na sodíku metabolismus   genetika   MeSH
• protein 1 přenášející organické anionty metabolismus   genetika   MeSH
• pyrazoly * farmakologie   MeSH
• pyridony * aplikace a dávkování   metabolismus   farmakologie   MeSH
• sexuální faktory MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.

• MeSH
• cholesterol * metabolismus   krev   MeSH
• cytochrom P-450 CYP3A metabolismus   genetika   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• hypercholesterolemie * farmakoterapie   metabolismus   MeSH
• hypolipidemika farmakologie   terapeutické užití   MeSH
• játra metabolismus   účinky léků   MeSH
• konstitutivní androstanový receptor * MeSH
• lidé MeSH
• metabolismus lipidů účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pregnanový X receptor * metabolismus   genetika   MeSH
• pyridiny MeSH
• receptory cytoplazmatické a nukleární * metabolismus   agonisté   genetika   MeSH
• regulace genové exprese účinky léků   MeSH
• žlučové kyseliny a soli * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The cardioselective β-1 receptor antagonist metoprolol is used to treat heart failure. It is metabolized in the liver, primarily by cytochrome 2D6. RESEARCH DESIGN AND METHODS: In this study, trough serum concentrations of metoprolol and its metabolite α-hydroxymetoprolol were measured in patients with heart failure with reduced ejection fraction. RESULTS: Concentrations were 1.3-122.9 μg/L for metoprolol and 1.3-125.7 μg/L for α-hydroxymetoprolol, metabolic ratios were 0.11-98.32. The median weight-adjusted apparent clearance of metoprolol was 53.07 (range 3.24-500.0). Metoprolol and α-hydroxymetoprolol concentrations correlated with both daily dose and dose per kilogram of body weight. However, metoprolol concentrations at the same daily dose showed a wide variability. Patients taking 100 mg/day had significantly lower NT-proBNP values than those taking 25 or 50 mg/day. Patients with LVEF ≤ 35% versus > 35% used significantly lower daily doses and doses per kilogram of body weight, although metoprolol concentrations did not differ. A poor cytochrome 2D6 metabolizer phenotype was detected in two patients. CONCLUSIONS: Metoprolol concentrations showed a wide interindividual variability at the same daily dose. Simultaneous determination of metoprolol and α-hydroxymetoprolol concentrations could identify patients at risk of possible accumulation of metoprolol leading to intoxication or, conversely, patients at risk of underdosing. [Figure: see text].

• MeSH
• antagonisté beta-1-adrenergních receptorů * aplikace a dávkování   MeSH
• cytochrom P-450 CYP2D6 metabolismus   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoprolol * aplikace a dávkování   farmakokinetika   analogy a deriváty   farmakologie   MeSH
• natriuretický peptid typu B * krev   MeSH
• peptidové fragmenty krev   MeSH
• pilotní projekty MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srdeční selhání * farmakoterapie   patofyziologie   MeSH
• tepový objem * účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Onosma riedliana Binzet & Orcan, a traditionally used plant species, has been explored for its therapeutic potential in this study. The work presented here is the first report on the phenolic profile and biological activity of this species. Three extracts of varying polarity were prepared, with the methanolic extract containing the highest phenolic content (97.62 ± 0.20 mgGAE/g). Key phenolic compounds identified included pinoresinol, hesperidin, 4-hydroxybenzoic acid, and p-coumaric acid. The methanolic extract exhibited exceptional antioxidant properties, rivaling Trolox as a positive control, primarily attributed to hesperidin and luteolin. Moreover, the ethyl acetate extract demonstrated remarkable inhibition of cholinesterase and tyrosinase enzymes, while the methanolic extract displayed potent activity against carbohydrate hydrolytic enzymes, α-amylase and α-glucosidase. Again, phenolic compounds were shown to be responsible for the inhibition of cholinesterases and tyrosinase, but not for α-amylase and α-glucosidase. These findings underscore Onosma riedliana's potential for incorporation into diverse pharmaceutical formulations, given its multifaceted bioactivity.

• MeSH
• alfa-amylasy MeSH
• alfa-glukosidasy MeSH
• antioxidancia farmakologie   MeSH
• fenoly farmakologie   MeSH
• hesperidin * MeSH
• inhibitory enzymů * farmakologie   MeSH
• methanol MeSH
• rostlinné extrakty farmakologie   MeSH
• tyrosinasa metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH