Biological and Pharmaceutical Bulletin, 2001, Vol.24(11), pp.1263-1266
2001
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Identification of Human Drug-Metabolizing Enzymes Involved in the Metabolism of SNI-2011
- Ist Teil von
- Biological and Pharmaceutical Bulletin, 2001, Vol.24(11), pp.1263-1266
- Ort / Verlag
- Tokyo: The Pharmaceutical Society of Japan
- Erscheinungsjahr
- 2001
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- In vitro studies were conducted to identify human drug-metabolizing enzymes involved in the metabolism of SNI-2011 ((±)-cis-2-methylspiro [1,3-oxathiolane-5,3'-quinuclidine] monohydrochloride hemihydrate, cevimeline hydrochloride hydrate). When 14C-SNI-2011 was incubated with human liver microsomes, SNI-2011 trans-sulfoxide and cis-sulfoxide were detected as major metabolites. These oxidations required NADPH, and were markedly inhibited by SKF-525A, indicating that cytochrome P450 (CYP) was involved. In a chemical inhibition study, metabolism of SNI-2011 in liver microsomes was inhibited (35-65%) by CYP3A4 inhibitors (ketoconazole and troleandomycin) and CYP2D6 inhibitors (quinidine and chlorpromazine). Furthermore, using microsomes containing cDNA-expressed CYPs, it was found that high rates of sulfoxidation activities were observed with CYP2D6 and CYP3A4. On the other hand, when 14C-SNI-2011 was incubated with human kidney microsomes, SNI-2011 N-oxide was identified as a major metabolite. This N-oxidation required NADPH, and was completely inhibited by thiourea, indicating that flavin-containing monooxygenase (FMO) was involved. In addition, microsomes containing cDNA-expressed FMO1, a major isoform in human kidney, mainly catalyzed N-oxidation of SNI-2011, but microsomes containing FMO3, a major isoform in adult human liver, did not. These results suggest that SNI-2011 is mainly catalyzed to sulfoxides and N-oxide by CYP2D6/3A4 in liver and FMO1 in kidney, respectively.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0918-6158eISSN: 1347-5215DOI: 10.1248/bpb.24.1263Titel-ID: cdi_proquest_miscellaneous_72307160
- Format
- –
- Schlagworte
- Animals, Biological and medical sciences, Cholinergic system, Cytochrome P-450 Enzyme System - biosynthesis, Cytochrome P-450 Enzyme System - genetics, Cytochrome P-450 Enzyme System - metabolism, cytochrome P450, DNA, Complementary - biosynthesis, Enzyme Inhibitors - pharmacology, flavin-containing monooxygenase, General pharmacology, human kidney microsome, human liver microsome, Humans, Insecta, Isoenzymes - biosynthesis, Isoenzymes - genetics, Isoenzymes - metabolism, Kidney - cytology, Kidney - drug effects, Kidney - enzymology, Medical sciences, Microsomes - drug effects, Microsomes - enzymology, Microsomes, Liver - drug effects, Microsomes, Liver - enzymology, Muscarinic Agonists - chemistry, Muscarinic Agonists - metabolism, Neuropharmacology, Neurotransmitters. Neurotransmission. Receptors, Oxygenases - biosynthesis, Oxygenases - genetics, Oxygenases - metabolism, Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions, Pharmacology. Drug treatments, Quinuclidines - antagonists & inhibitors, Quinuclidines - chemistry, Quinuclidines - metabolism, SNI-2011, Thiophenes