• Archives of Pharmacal Research
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• v.23 no.3
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• pp.230-236
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• 2000

(1'R, 2R)-, (1'R, 2S)-, (1'S, 2R)- and (1'S, 2S)-$\alpha$-hydroxymetoprolol; (2R)- and (2S)-O-des-methylmetoprolol; and (2R)- and (2S)-metoprolol acid are major metabolites of (2R)-and (2S)-metoprolol, $\beta$-adrenergic antagonist. The focus of most chiral separation methods until now has been on determination of the enantiomeric parent drug. However, it is just as important to be able to follow the metabolism of the enantiomers and their possible chiral metabolites. Therefore, for the study of stereoselective metabolism and pharmacokinetics of metoprolol, the chiral separation of the enantiomers of metoprolol and its metabolites has been investigated using four chiral stationary phases, i.e., Chiralcel OD, Chiral-AGP, Cyclobond I and Sumichiral OA-4900 columns. Metoprolol acid was resolved only by Sumichiral OA-4900. Chiralcel OD provided the highest separation factor and resolution value for metoprolol and O-desmethylmetoprolol and partially resolved the four stereoisomers of $\alpha$-hydroxymetoprolol. Diastereomeric $\alpha$-hydroxymetoprolols were resolved using the coupled column chromatographic system of two chiral stationary phases, Sumichiral OA-4900 column and Chiralcel OD column.

• Archives of Pharmacal Research
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• v.23 no.3
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• pp.226-229
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• 2000

To obtain the standard compounds of metoprolol for a pharmacokinetic study, a convenient synthetic procedure to prepare enantiomers of metoprolol (3a) and its major metaboites, 2-4-(2-hydroxy-3-isopropylamino)propoxyphenylathanol (3b) and 4-(2-hydroxy-3- isopropylamino) pro-poxyphenylacetic acid (4), was developed from their respective starting materials, 4-(2-methoxyethyl)phenol (1a), 4-(2-hydroxyethyl)phenol (1b) and methyl 4-hydroxyphenylacetate (1c). These phenolic compounds (1a, b, c) were converted in situ to their corresponding phenoxides with sodium hydroxide treatment followed by (R)- or (S)-epichlorohydrin treatment. The resulting epoxides 2 were transformed to 3 through reaction with isopropylamine. Ester 3c was hydrolyzed to the metabolite 4. Measured using the HPLC method on chiral column without any derivatization, the optical purity of enantiomers of metoprolol and o-demethylated metabolite 3b ranged between 96-99 ％ ee and that of enantiomers of carboxylic acid metabolite 4 ranged 91％ ee.

• Journal of Environmental Analysis, Health and Toxicology
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• v.21 no.4
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• pp.243-251
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• 2018

Pharmaceuticals in wastewater effluents have been recognized as emerging pollutants threatening freshwater organisms. To extend understanding for bioaccumulation and toxicity in those organisms, information on biotransformation products (or metabolites) and their metabolic pathway are crucial. The aim of the present study is to identify and elucidate metabolites of pharmaceuticals formed in exposed organisms using suspect and nontarget screening approach using LC-HRMS. As the target pharmaceuticals, carbamazepine, ketoprofen, metoprolol, propranolol, and verapamil were selected whereas Daphnia magna and Gammarus pulex were used as test organisms. After 24h exposure, metabolites formed in the organisms were identified using LC-HRMS. The structures of metabolites were elucidated via analysis of MS/MS fragment pattern and the comparison with fragment database. As the results, a total of 10 metabolites were identified for 5 parent compounds (C253/C356 for carbamazepine, K211 for ketoprofen, M256 for metoprolol, P218/P276/P306 for propranolol, V196/V291/V441 for verapamil). Among them, the presence of C253 and V291 was confirmed using standard materials. Most of the identified metabolites were formed through oxidative reactions such as hydroxylation, N-demethylation, and dealkylation. Cysteine conjugation (phase II reaction) metabolite (C356) for carbamazepine was found in daphnia. The metabolic pathway of verapamil showed similar metabolic pathways and metabolic pathways for both species. Although the toxicological information on the identified metabolites could not be confirmed, the molecular structure information of the proposed metabolites can be used for future evaluation and prediction of toxicity.