Pharmaceuticals are a large group of substances that have been recognized as environmental contaminants in recent years. Research on the pharmaceutical fate in soils is currently limited or missing. In this study, three pharmaceuticals (atenolol (ATE), carbamazepine (CAR), and metoprolol (MET)) were introduced to soils and exposed for 61 day under aerobic conditions. Thirteen different soils were used in the study to increase the understanding of pharmaceutical behaviour in the soil matrix. Ten metabolites were detected and tentatively identified. Some of them, such as atenolol acid (AAC), carbamazepine 10,11-epoxide (EPC), 10,11-dihydrocarbamazepine (DHC), trans-10,11-Dihydro-10,11-dihydroxy carbamazepine (RTC), and metoprolol acid (MAC), were consequently confirmed using commercial reference standards. It was concluded that the aerobic conditions of the experiment determined the pharmaceutical degradation pathway of studied compounds in the soils. The different amounts/rates and degradation of the transformation products can be attributed to differences in the soil properties. ATE degraded relatively quickly compared with CAR, whereas MET degradation in the soils was unclear. The persistence of CAR and its metabolites, in combination with low CAR sorption, enable the transportation of CAR and its metabolites within soils and into the ground water. Thus, CAR may cause adverse effects on the environment and humans.
Metabolický pomer (MR) metoprololu/?-hydroxymetoprololu za 3 hod po užití jednorázovej dávky metoprololu sa používa na stanovenie fenotypu enzýmu cytochrómu P450 2D6. Cieľom tejto práce bolo porovnať metabolickú aktivitu cytochrómu P450 2D6 po prvom a opakovanom užití metoprololu. Do tejto práce bolo zahrnutých 13 pacientov s hypertenziou (7 žien), u ktorých bolo plánované nasadenie beta-blokátora metoprololu. Vek (priemer ± SD) bol 42,8 ± 12,9 rokov, telesná hmotnosť (priemer ± SD) bola 94,0 ± 25,4 kg. Dávka metoprololu bola u každého pacienta zvolená na základe klinického stavu pacienta v deň užitia prvej tablety. Krvné odbery boli urobené po užití prvej dávky metoprololu a najmenej 2 týždne od nasadenia metoprololu k zaručeniu ustáleného stavu (opakované užívanie). Na základe hodnôt MR boli všetci pacienti po jednorázovom i opakovanom užití zaradení do tej istej fenotypovej skupiny. Pozorovali sme tesnú koreláciu medzi MR po jednorázovom a opakovanom užití metoprololu (rs = 0,8418, P = 0,0003). Všetci pacienti boli v oboch odberoch zaradení do rovnakej fenotypovej skupiny, extenzivný metabolizátor i napriek signifikantnému rozdielu medzi MR metoprololu/?-hydroxymetoprololu po jednorázovom a opakovanom užití (medián 0,59 vs. 0,81, P = 0,0266), Využitie MR metoprololu/?-hydroxymetoprololu u pacientov na dlhodobej terapii metoprololom je vhodné pre stanovenie fenotypu enzýmu cytochrómu P450 2D6.
Metoprolol/?-hydroxymetoprolol metabolic ratio (MR) 3 hours after a single metoprolol dose is used for cytochrome P450 2D6 phenotyping. The aim was to compare cytochrome P450 2D6 metabolic activity after the first metoprolol dose and in steady state. Thirteen adult hypertensive patients (7 females) in whom an introduction of the beta-blocker metoprolol was indicated were included. Age (mean ± SD) was 42.8 ± 12.9 years, weight (mean ± SD) was 94.0 ± 25.4 kg. Metoprolol dose was chosen based on clinical grounds on the day of metoprolol first ingestion. Blood samples were drawn after the first dose and at least 2 weeks since metoprolol introduction to ensure steady state. The patients were phenotyped as extensive metabolizers in both periods, after metoprolol first ingestion and in steady state. We observed a significant correlation (rs = 0.8418, P = 0.0003) between the metoprolol/?-hydroxymetoprolol MRs. All the patients were phenotyped as extensive metabolizers in both periods, despite statistically significant differences between the median MRs (0.59 versus 0.81, P = 0.0266). The differences were not of such an extent so as to assign subjects to different phenotypic groups. Metoprolol/?-hydroxymetoprolol MR in steady state is an appropriate alternative to metoprolol/?-hydroxymetoprolol MR after a single dose.
Beta-blokátory patria medzi základné liečivá v terapii kardiovaskulárnych ochorení. Ich spoločný mechanizmus účinku je založený na blokáde ß-adrenergných receptorov. Avšak v rámci skupiny beta-blokátorov existujú medzi jednotlivými látkami farmakokinetické a farmakodynamické rozdiely, ktoré sú klinicky relevantné. Naviac odpoveď na beta-blokátor sa môže medzi pacientmi líšiť. Na tom má určitý podiel genetický polymorfizmus biotransformačných enzýmov cytochrómu P450 (ďalej len P450), vrátane P450 2D6, ktorým sa biotransformuje niekoľko bežne užívaných beta-blokátorov. Poznanie vlastností a teda odlišností medzi beta-blokátormi je nevyhnutné pre ich správne klinické využitie.
Beta-adrenergic blockers rank among the principal drugs in the treatment of cardiovascular diseases. Their common mechanism of action is based on the ß-adrenergic receptor blockade. However, differences in pharmacokinetic and pharmacodynamic properties exist between the individual agents in the beta-blocker class, and these differences may be of clinical relevance. In addition, responses to beta-blockers are variable among patients. Genetic plymorphism in drug-metabolizing enzymes, including cytochrome P450 2D6, has been demonstrated to contribute to the variability of several beta-blockers. The understanding of beta-blocker properties and their differences is thus important for their proper clinical use.
- MeSH
- beta blokátory farmakokinetika farmakologie škodlivé účinky MeSH
- betaxolol metabolismus MeSH
- biotransformace účinky léků MeSH
- cytochrom P-450 CYP2D6 účinky léků MeSH
- hypertenze farmakoterapie MeSH
- lidé MeSH
- metoprolol metabolismus MeSH
- polymorfismus genetický MeSH
- srdeční arytmie farmakoterapie MeSH
- srdeční selhání farmakoterapie MeSH
- timolol metabolismus MeSH
- Check Tag
- lidé MeSH
- MeSH
- biologické markery krev metabolismus moč MeSH
- časové faktory MeSH
- cytochrom P-450 CYP2D6 metabolismus účinky léků MeSH
- lidé MeSH
- metabolická inaktivace fyziologie genetika MeSH
- metabolismus genetika účinky léků MeSH
- metoprolol krev metabolismus moč MeSH
- odběr vzorku krve metody využití MeSH
- polymorfismus genetický genetika účinky léků MeSH
- sérum metabolismus účinky léků MeSH
- vysokoúčinná kapalinová chromatografie metody využití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- abstrakty MeSH
V práci je popsána metoda vysokoúčinné kapalinové chromatografie, která byla zavedena pro účely fenotypizace enzymu CYP2D6 metoprololem jako substrátovou látkou. Metoprolol, ?-hydroxmetoprolol a nadolol (vnitřní standard) byly extrahovány ze séra dichlormethanem s přídavkem 1 mol/l NaOH. Látky byly separovány na koloně s reverzní fází SupercosilTM LC-18 (15 cm × 3 mm, 5 µm) mobilní fází o složení acetonitril : methanol : voda : triethylamin (15 : 5 : 80 : 0,1; pH 3,0) při průtoku 0,7 ml/min. Fluorescenční detekce (FL) probíhala při vlnové délce 230 nm (excitační) a 300 nm (emisní). Celková doba analýzy byla 12 min. Retenční časy byly pro ?-hydroxymetoprolol (h-MET) 2,04 minut, pro nadolol (IS) 3,02 minut a pro metoprolol (MET) 9,04 minut. Přesnosti v sérii a mezi sériemi vyjádřené jako relativní směrodatné odchylky byly nižší než 7,2 % a recovery se pohybovalo v rozmezí 98,2–103,0 %. Kalibrační křivka byla lineární v rozmezí 25–500 ng/ml (r = 0,999) pro obě látky. Detekční limit byl stanoven pro metoprolol a ?-hydroxymetoprolol na 5 ng/ml a kvantifikační limit na 25 ng/ml. Prezentovaná metoda může být vhodná pro analýzu metoprololu a ?-hydroxymetoprololu v séru u pacientů s hypertenzí, ICHS i jiných onemocnění.
High-performance liquid chromatography method has been developed with a view of its future use in the phenotyping of CYP2D6 enzyme by metoprolol as a probe drug. Metoprolol, ?-hydroxymetoprolol and the internal standard nadolol were extracted from serum with dichloromethane alkalinized with 1 mol/l NaOH. Chromatographic separations were performed on the reversed-phase column SupercosilTM LC-18 (15 cm × 3 mm, 5 µm) with the mobile phase containing acetonitril : methanol : water : triethylamine (15 : 5 : 80 : 0.1, pH 3.0) at a flow rate of 0.7 ml/min. Fluorescence detection (FL) was made at 230 nm (excitation) and 300 nm (emission). The total analysis time was 12 min. The retention time for ?-hydroxymetoprolol, nadolol and metoprolol were 2.04, 3.02 and 9.04 min, respectively. The intra-assay and inter-assay precisions (coefficients of variation) were less than 7.2 %, and recovery values were found to be within 98.2–103.0 %. The calibration curve of the method was linear over a concentration range of 25–500 ng/ml (r = 0.999) for both compounds. The limit of detection was 5 ng/ml and the limit of quantification was 25 ng/ml for both metoprolol and ?-hydroxymetoprolol. The reported method could be suitable for measurements of metoprolol and ?-hydroxymetoprolol in serum from patients with hypertension, IHD and other illnesses.
