In-vitro metabolism of the new anxiolytic agent, RWJ-50172, in rat hepatic S9 fraction and microbial transformation in fungi, Cunninghamella sp
The in‐vitro biotransformation of the anxiolytic agent, RWJ‐50172 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH‐generating system, and incubating with Cunninghamella echinulata in soy‐bean medium. Unchanged RWJ‐50172 (80% of the sample in rat; 86% in fungi) pl...
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| Veröffentlicht in: | Journal of pharmacy and pharmacology 2003-08, Vol.55 (8), p.1099-1105 |
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| creator | Wu, Wu-Nan McKown, Linda A. Melton, John L. Reitz, Allen B. |
| description | The in‐vitro biotransformation of the anxiolytic agent, RWJ‐50172 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH‐generating system, and incubating with Cunninghamella echinulata in soy‐bean medium. Unchanged RWJ‐50172 (80% of the sample in rat; 86% in fungi) plus 6 metabolites (M1‐M6) were profiled, quantified and tentatively identified on the basis of API‐MS/MS data. The metabolic pathways for RWJ‐50172 are proposed, and the four metabolic pathways are: pyrido‐oxidation (pathway A), phenylhydroxylation (B), dehydration (C) and reduction (D). Pathway A formed hydroxy‐pyrido‐RWJ‐50172 (M1, 10% of the sample in both rat and fungi) as the only major metabolite, which further dehydrated to form dehydro‐RWJ‐50172 in trace quantities in rat. Pathway B produced hydroxyphenyl‐RWJ‐50172 (M2) in small amounts (4%) in rat, and in conjunction with step A formed dihydroxy‐RWJ‐50172 as a trace metabolite in rat. Step D produced a minor benzimidazole‐reduced metabolite in fungi. RWJ‐50172 is substantially metabolized by this rat hepatic S9 fraction and fungi. |
| doi_str_mv | 10.1211/002235703322277122 |
| format | Article |
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Unchanged RWJ‐50172 (80% of the sample in rat; 86% in fungi) plus 6 metabolites (M1‐M6) were profiled, quantified and tentatively identified on the basis of API‐MS/MS data. The metabolic pathways for RWJ‐50172 are proposed, and the four metabolic pathways are: pyrido‐oxidation (pathway A), phenylhydroxylation (B), dehydration (C) and reduction (D). Pathway A formed hydroxy‐pyrido‐RWJ‐50172 (M1, 10% of the sample in both rat and fungi) as the only major metabolite, which further dehydrated to form dehydro‐RWJ‐50172 in trace quantities in rat. Pathway B produced hydroxyphenyl‐RWJ‐50172 (M2) in small amounts (4%) in rat, and in conjunction with step A formed dihydroxy‐RWJ‐50172 as a trace metabolite in rat. Step D produced a minor benzimidazole‐reduced metabolite in fungi. RWJ‐50172 is substantially metabolized by this rat hepatic S9 fraction and fungi.</description><identifier>ISSN: 0022-3573</identifier><identifier>EISSN: 2042-7158</identifier><identifier>DOI: 10.1211/002235703322277122</identifier><identifier>PMID: 12956899</identifier><identifier>CODEN: JPPMAB</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Amides - metabolism ; Amides - pharmacokinetics ; Animals ; Anti-Anxiety Agents - metabolism ; Anti-Anxiety Agents - pharmacokinetics ; Benzimidazoles - metabolism ; Benzimidazoles - pharmacokinetics ; Biological and medical sciences ; Biotransformation ; Cunninghamella - enzymology ; Cunninghamella - metabolism ; In Vitro Techniques ; Male ; Medical sciences ; Microsomes, Liver - metabolism ; Neuropharmacology ; Pharmacology. Drug treatments ; Psycholeptics: tranquillizer, neuroleptic ; Psychology. Psychoanalysis. 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Unchanged RWJ‐50172 (80% of the sample in rat; 86% in fungi) plus 6 metabolites (M1‐M6) were profiled, quantified and tentatively identified on the basis of API‐MS/MS data. The metabolic pathways for RWJ‐50172 are proposed, and the four metabolic pathways are: pyrido‐oxidation (pathway A), phenylhydroxylation (B), dehydration (C) and reduction (D). Pathway A formed hydroxy‐pyrido‐RWJ‐50172 (M1, 10% of the sample in both rat and fungi) as the only major metabolite, which further dehydrated to form dehydro‐RWJ‐50172 in trace quantities in rat. Pathway B produced hydroxyphenyl‐RWJ‐50172 (M2) in small amounts (4%) in rat, and in conjunction with step A formed dihydroxy‐RWJ‐50172 as a trace metabolite in rat. Step D produced a minor benzimidazole‐reduced metabolite in fungi. RWJ‐50172 is substantially metabolized by this rat hepatic S9 fraction and fungi.</description><subject>Amides - metabolism</subject><subject>Amides - pharmacokinetics</subject><subject>Animals</subject><subject>Anti-Anxiety Agents - metabolism</subject><subject>Anti-Anxiety Agents - pharmacokinetics</subject><subject>Benzimidazoles - metabolism</subject><subject>Benzimidazoles - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Cunninghamella - enzymology</subject><subject>Cunninghamella - metabolism</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - metabolism</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Psycholeptics: tranquillizer, neuroleptic</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>0022-3573</issn><issn>2042-7158</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcuO0zAUhiMEYsrAC7BA3sCqAfs4vi1RBXNRBcNw6dJyHKc1JE6xE2b6FLwyLq2YBQvY2Ivzfcc-5y-KpwS_JEDIK4wBKBOYUgAQggDcK2aAKygFYfJ-MdsDZSboSfEopa8YY8E5f1icEFCMS6Vmxc-LUP7wYxxQ70ZTD51PPRpaNG4cCu4GmXDrh243eovM2oVxjq5XlyXDRMAc-YCiGdHGbc0e-KhQG40d_RCy16De2zjU3nRojCakdoi9-V3MXjuFtZ-jxRSCD-uN6V3XGZS2j4sHremSe3K8T4vPb998WpyXy_dnF4vXy9JWioiStVJKZSxTrXCqwpXEdT6sVZaBaCR3eUOKUSatwy03vAaSiw00NfCm5fS0eHHou43D98mlUfc-2f0nghumpAVllWSE_BMETFQlFWQQDmAeOqXoWr2NvjdxpwnW-7z033ll6dmx-1T3rrlTjgFl4PkRMMmaLu83WJ_uOJYzBb6fRx64G9-53X88rS-vzq9AUJHV8qD6NLrbP6qJ3zTPdaZX7840-bCiZMmu9Rf6C4b-u0Q</recordid><startdate>200308</startdate><enddate>200308</enddate><creator>Wu, Wu-Nan</creator><creator>McKown, Linda A.</creator><creator>Melton, John L.</creator><creator>Reitz, Allen B.</creator><general>Blackwell Publishing Ltd</general><general>Pharmaceutical Press</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T7</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>200308</creationdate><title>In-vitro metabolism of the new anxiolytic agent, RWJ-50172, in rat hepatic S9 fraction and microbial transformation in fungi, Cunninghamella sp</title><author>Wu, Wu-Nan ; McKown, Linda A. ; Melton, John L. ; Reitz, Allen B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4917-5f8889ac59f7e940480b048cc9c527d86e12195358ce0f6a6b21cc9d2db26df63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Amides - metabolism</topic><topic>Amides - pharmacokinetics</topic><topic>Animals</topic><topic>Anti-Anxiety Agents - metabolism</topic><topic>Anti-Anxiety Agents - pharmacokinetics</topic><topic>Benzimidazoles - metabolism</topic><topic>Benzimidazoles - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Cunninghamella - enzymology</topic><topic>Cunninghamella - metabolism</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - metabolism</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Psycholeptics: tranquillizer, neuroleptic</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Wu-Nan</creatorcontrib><creatorcontrib>McKown, Linda A.</creatorcontrib><creatorcontrib>Melton, John L.</creatorcontrib><creatorcontrib>Reitz, Allen B.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of pharmacy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Wu-Nan</au><au>McKown, Linda A.</au><au>Melton, John L.</au><au>Reitz, Allen B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In-vitro metabolism of the new anxiolytic agent, RWJ-50172, in rat hepatic S9 fraction and microbial transformation in fungi, Cunninghamella sp</atitle><jtitle>Journal of pharmacy and pharmacology</jtitle><addtitle>J Pharm Pharmacol</addtitle><date>2003-08</date><risdate>2003</risdate><volume>55</volume><issue>8</issue><spage>1099</spage><epage>1105</epage><pages>1099-1105</pages><issn>0022-3573</issn><eissn>2042-7158</eissn><coden>JPPMAB</coden><abstract>The in‐vitro biotransformation of the anxiolytic agent, RWJ‐50172 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH‐generating system, and incubating with Cunninghamella echinulata in soy‐bean medium. Unchanged RWJ‐50172 (80% of the sample in rat; 86% in fungi) plus 6 metabolites (M1‐M6) were profiled, quantified and tentatively identified on the basis of API‐MS/MS data. The metabolic pathways for RWJ‐50172 are proposed, and the four metabolic pathways are: pyrido‐oxidation (pathway A), phenylhydroxylation (B), dehydration (C) and reduction (D). Pathway A formed hydroxy‐pyrido‐RWJ‐50172 (M1, 10% of the sample in both rat and fungi) as the only major metabolite, which further dehydrated to form dehydro‐RWJ‐50172 in trace quantities in rat. Pathway B produced hydroxyphenyl‐RWJ‐50172 (M2) in small amounts (4%) in rat, and in conjunction with step A formed dihydroxy‐RWJ‐50172 as a trace metabolite in rat. Step D produced a minor benzimidazole‐reduced metabolite in fungi. RWJ‐50172 is substantially metabolized by this rat hepatic S9 fraction and fungi.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>12956899</pmid><doi>10.1211/002235703322277122</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Amides - metabolism Amides - pharmacokinetics Animals Anti-Anxiety Agents - metabolism Anti-Anxiety Agents - pharmacokinetics Benzimidazoles - metabolism Benzimidazoles - pharmacokinetics Biological and medical sciences Biotransformation Cunninghamella - enzymology Cunninghamella - metabolism In Vitro Techniques Male Medical sciences Microsomes, Liver - metabolism Neuropharmacology Pharmacology. Drug treatments Psycholeptics: tranquillizer, neuroleptic Psychology. Psychoanalysis. Psychiatry Psychopharmacology Rats Rats, Sprague-Dawley |
| title | In-vitro metabolism of the new anxiolytic agent, RWJ-50172, in rat hepatic S9 fraction and microbial transformation in fungi, Cunninghamella sp |
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