Glucuronidation of tizoxanide, an active metabolite of nitazoxanide, in liver and small intestine: Species differences in humans, monkeys, dogs, rats, and mice and responsible UDP-glucuronosyltransferase isoforms in humans
Tizoxanide (TZX) is an active metabolite of nitazoxanide (NTZ) originally developed as an antiparasitic agent, and is predominantly metabolized into TZX glucuronide. In the present study, TZX glucuronidation by the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice, and recombi...
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| creator | Hanioka, Nobumitsu Isobe, Takashi Saito, Keita Nagaoka, Kenjiro Mori, Yoko Jinno, Hideto Ohkawara, Susumu Tanaka-Kagawa, Toshiko |
| description | Tizoxanide (TZX) is an active metabolite of nitazoxanide (NTZ) originally developed as an antiparasitic agent, and is predominantly metabolized into TZX glucuronide. In the present study, TZX glucuronidation by the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice, and recombinant human UDP-glucuronosyltransferase (UGT) were examined. The kinetics of TZX glucuronidation by the liver and intestinal microsomes followed the Michaelis–Menten or biphasic model, with species-specific variations in the intrinsic clearance (CLint). Rats and mice exhibited the highest CLint values for liver microsomes, while mice and rats were the highest for intestinal microsomes. Among human UGTs, UGT1A1 and UGT1A8 demonstrated significant glucuronidation activity. Estradiol and emodin inhibited TZX glucuronidation activities in the human liver and intestinal microsomes in a dose-dependent manner, with emodin showing stronger inhibition in the intestinal microsomes. These results suggest that the roles of UGT enzymes in TZX glucuronidation in the liver and small intestine differ extensively across species and that UGT1A1 and/or UGT1A8 mainly contribute to the metabolism and elimination of TZX in humans. This study presents the relevant and novel-appreciative report on TZX metabolism catalyzed by UGT enzymes, which may aid in the assessment of the antiparasitic, antibacterial, and antiviral activities of NTZ for the treatment of various infections.
[Display omitted]
•TZX glucuronidation abilities in the liver and small intestine differ extensively across species.•TZX glucuronidation activities in the liver microsomes were rats > mice ≥ monkeys > dogs > humans.•TZX glucuronidation activities in the intestinal microsomes were mice ≥ rats > monkeys > dogs > humans.•UGT1A1 and/or UGT1A8 mainly contribute to the metabolism and elimination of TZX in humans. |
| doi_str_mv | 10.1016/j.cbpc.2024.109962 |
| format | Article |
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[Display omitted]
•TZX glucuronidation abilities in the liver and small intestine differ extensively across species.•TZX glucuronidation activities in the liver microsomes were rats > mice ≥ monkeys > dogs > humans.•TZX glucuronidation activities in the intestinal microsomes were mice ≥ rats > monkeys > dogs > humans.•UGT1A1 and/or UGT1A8 mainly contribute to the metabolism and elimination of TZX in humans.</description><identifier>ISSN: 1532-0456</identifier><identifier>EISSN: 1878-1659</identifier><identifier>DOI: 10.1016/j.cbpc.2024.109962</identifier><identifier>PMID: 38889874</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Antiparasitic Agents - metabolism ; Dogs ; Female ; Glucuronidation ; Glucuronides - metabolism ; Glucuronosyltransferase - metabolism ; Humans ; Intestinal microsomes ; Intestine, Small - drug effects ; Intestine, Small - enzymology ; Intestine, Small - metabolism ; Isoenzymes - metabolism ; Liver - drug effects ; Liver - enzymology ; Liver - metabolism ; Liver microsomes ; Macaca fascicularis ; Male ; Mice ; Microsomes - enzymology ; Microsomes - metabolism ; Microsomes, Liver - metabolism ; Nitazoxanide (NTZ) ; Nitro Compounds - metabolism ; Rats ; Rats, Sprague-Dawley ; Species Specificity ; Thiazoles - metabolism ; Tizoxanide (TZX) ; UDP-glucuronosyltransferase (UGT)</subject><ispartof>Comparative biochemistry and physiology. Toxicology & pharmacology, 2024-09, Vol.283, p.109962, Article 109962</ispartof><rights>2024 Elsevier Inc.</rights><rights>Copyright © 2024 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c237t-6a503313fa14cc1554baf4072d3b93f05af0847a10af5e2c7dc1b8e1b837e3d93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cbpc.2024.109962$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38889874$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hanioka, Nobumitsu</creatorcontrib><creatorcontrib>Isobe, Takashi</creatorcontrib><creatorcontrib>Saito, Keita</creatorcontrib><creatorcontrib>Nagaoka, Kenjiro</creatorcontrib><creatorcontrib>Mori, Yoko</creatorcontrib><creatorcontrib>Jinno, Hideto</creatorcontrib><creatorcontrib>Ohkawara, Susumu</creatorcontrib><creatorcontrib>Tanaka-Kagawa, Toshiko</creatorcontrib><title>Glucuronidation of tizoxanide, an active metabolite of nitazoxanide, in liver and small intestine: Species differences in humans, monkeys, dogs, rats, and mice and responsible UDP-glucuronosyltransferase isoforms in humans</title><title>Comparative biochemistry and physiology. Toxicology & pharmacology</title><addtitle>Comp Biochem Physiol C Toxicol Pharmacol</addtitle><description>Tizoxanide (TZX) is an active metabolite of nitazoxanide (NTZ) originally developed as an antiparasitic agent, and is predominantly metabolized into TZX glucuronide. In the present study, TZX glucuronidation by the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice, and recombinant human UDP-glucuronosyltransferase (UGT) were examined. The kinetics of TZX glucuronidation by the liver and intestinal microsomes followed the Michaelis–Menten or biphasic model, with species-specific variations in the intrinsic clearance (CLint). Rats and mice exhibited the highest CLint values for liver microsomes, while mice and rats were the highest for intestinal microsomes. Among human UGTs, UGT1A1 and UGT1A8 demonstrated significant glucuronidation activity. Estradiol and emodin inhibited TZX glucuronidation activities in the human liver and intestinal microsomes in a dose-dependent manner, with emodin showing stronger inhibition in the intestinal microsomes. These results suggest that the roles of UGT enzymes in TZX glucuronidation in the liver and small intestine differ extensively across species and that UGT1A1 and/or UGT1A8 mainly contribute to the metabolism and elimination of TZX in humans. This study presents the relevant and novel-appreciative report on TZX metabolism catalyzed by UGT enzymes, which may aid in the assessment of the antiparasitic, antibacterial, and antiviral activities of NTZ for the treatment of various infections.
[Display omitted]
•TZX glucuronidation abilities in the liver and small intestine differ extensively across species.•TZX glucuronidation activities in the liver microsomes were rats > mice ≥ monkeys > dogs > humans.•TZX glucuronidation activities in the intestinal microsomes were mice ≥ rats > monkeys > dogs > humans.•UGT1A1 and/or UGT1A8 mainly contribute to the metabolism and elimination of TZX in humans.</description><subject>Animals</subject><subject>Antiparasitic Agents - metabolism</subject><subject>Dogs</subject><subject>Female</subject><subject>Glucuronidation</subject><subject>Glucuronides - metabolism</subject><subject>Glucuronosyltransferase - metabolism</subject><subject>Humans</subject><subject>Intestinal microsomes</subject><subject>Intestine, Small - drug effects</subject><subject>Intestine, Small - enzymology</subject><subject>Intestine, Small - metabolism</subject><subject>Isoenzymes - metabolism</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - metabolism</subject><subject>Liver microsomes</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Mice</subject><subject>Microsomes - enzymology</subject><subject>Microsomes - metabolism</subject><subject>Microsomes, Liver - metabolism</subject><subject>Nitazoxanide (NTZ)</subject><subject>Nitro Compounds - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Species Specificity</subject><subject>Thiazoles - metabolism</subject><subject>Tizoxanide (TZX)</subject><subject>UDP-glucuronosyltransferase (UGT)</subject><issn>1532-0456</issn><issn>1878-1659</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2OFCEUhStG44yjL-DCsHTR1UJR1I9xMxl1NJlEE501oeAy0lLQAjWxfVifxdvT7c_KBXBy890T7j1V9ZTRNaOse7FZ62mr1w1tWiyMY9fcq07Z0A8168R4H7XgTU1b0Z1Uj3LeUEpFy7qH1QkfhmEc-va0-nnpF72kGJxRxcVAoiXF_YjfFVZgRVQgShd3C2SGoqboXYE9E1xRfykXiEcmIW5InpX3WCqQiwvwknzagnaQiXHWQoKgUWPHl2VWIa_IHMNX2KEw8QbvpEpe3RnNTsOdSJC3MWQ3eSDXrz_WN8c_x7zzJaEJ2qoMxOVoY5r_cX9cPbDKZ3hyfM-q67dvPl-8q68-XL6_OL-qdcP7UndKUM4Zt4q1WjMh2knZlvaN4dPILRXK0qHtFaPKCmh0bzSbBsDDe-Bm5GfV84PvNsVvCw4uZ5c1eK8CxCVLTnvaj303CESbA6pTzDmBldvkZpV2klG5z1Vu5D5Xuc9VHnLFpmdH_2Wawfxp-R0kAq8OAOCUtw6SzLhzXLVxCXSRJrr_-f8CZ5C6BQ</recordid><startdate>202409</startdate><enddate>202409</enddate><creator>Hanioka, Nobumitsu</creator><creator>Isobe, Takashi</creator><creator>Saito, Keita</creator><creator>Nagaoka, Kenjiro</creator><creator>Mori, Yoko</creator><creator>Jinno, Hideto</creator><creator>Ohkawara, Susumu</creator><creator>Tanaka-Kagawa, Toshiko</creator><general>Elsevier Inc</general><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>7X8</scope></search><sort><creationdate>202409</creationdate><title>Glucuronidation of tizoxanide, an active metabolite of nitazoxanide, in liver and small intestine: Species differences in humans, monkeys, dogs, rats, and mice and responsible UDP-glucuronosyltransferase isoforms in humans</title><author>Hanioka, Nobumitsu ; Isobe, Takashi ; Saito, Keita ; Nagaoka, Kenjiro ; Mori, Yoko ; Jinno, Hideto ; Ohkawara, Susumu ; Tanaka-Kagawa, Toshiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c237t-6a503313fa14cc1554baf4072d3b93f05af0847a10af5e2c7dc1b8e1b837e3d93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Antiparasitic Agents - metabolism</topic><topic>Dogs</topic><topic>Female</topic><topic>Glucuronidation</topic><topic>Glucuronides - metabolism</topic><topic>Glucuronosyltransferase - metabolism</topic><topic>Humans</topic><topic>Intestinal microsomes</topic><topic>Intestine, Small - drug effects</topic><topic>Intestine, Small - enzymology</topic><topic>Intestine, Small - metabolism</topic><topic>Isoenzymes - metabolism</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Liver - metabolism</topic><topic>Liver microsomes</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Mice</topic><topic>Microsomes - enzymology</topic><topic>Microsomes - metabolism</topic><topic>Microsomes, Liver - metabolism</topic><topic>Nitazoxanide (NTZ)</topic><topic>Nitro Compounds - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Species Specificity</topic><topic>Thiazoles - metabolism</topic><topic>Tizoxanide (TZX)</topic><topic>UDP-glucuronosyltransferase (UGT)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hanioka, Nobumitsu</creatorcontrib><creatorcontrib>Isobe, Takashi</creatorcontrib><creatorcontrib>Saito, Keita</creatorcontrib><creatorcontrib>Nagaoka, Kenjiro</creatorcontrib><creatorcontrib>Mori, Yoko</creatorcontrib><creatorcontrib>Jinno, Hideto</creatorcontrib><creatorcontrib>Ohkawara, Susumu</creatorcontrib><creatorcontrib>Tanaka-Kagawa, Toshiko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Comparative biochemistry and physiology. Toxicology & pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hanioka, Nobumitsu</au><au>Isobe, Takashi</au><au>Saito, Keita</au><au>Nagaoka, Kenjiro</au><au>Mori, Yoko</au><au>Jinno, Hideto</au><au>Ohkawara, Susumu</au><au>Tanaka-Kagawa, Toshiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glucuronidation of tizoxanide, an active metabolite of nitazoxanide, in liver and small intestine: Species differences in humans, monkeys, dogs, rats, and mice and responsible UDP-glucuronosyltransferase isoforms in humans</atitle><jtitle>Comparative biochemistry and physiology. Toxicology & pharmacology</jtitle><addtitle>Comp Biochem Physiol C Toxicol Pharmacol</addtitle><date>2024-09</date><risdate>2024</risdate><volume>283</volume><spage>109962</spage><pages>109962-</pages><artnum>109962</artnum><issn>1532-0456</issn><eissn>1878-1659</eissn><abstract>Tizoxanide (TZX) is an active metabolite of nitazoxanide (NTZ) originally developed as an antiparasitic agent, and is predominantly metabolized into TZX glucuronide. In the present study, TZX glucuronidation by the liver and intestinal microsomes of humans, monkeys, dogs, rats, and mice, and recombinant human UDP-glucuronosyltransferase (UGT) were examined. The kinetics of TZX glucuronidation by the liver and intestinal microsomes followed the Michaelis–Menten or biphasic model, with species-specific variations in the intrinsic clearance (CLint). Rats and mice exhibited the highest CLint values for liver microsomes, while mice and rats were the highest for intestinal microsomes. Among human UGTs, UGT1A1 and UGT1A8 demonstrated significant glucuronidation activity. Estradiol and emodin inhibited TZX glucuronidation activities in the human liver and intestinal microsomes in a dose-dependent manner, with emodin showing stronger inhibition in the intestinal microsomes. These results suggest that the roles of UGT enzymes in TZX glucuronidation in the liver and small intestine differ extensively across species and that UGT1A1 and/or UGT1A8 mainly contribute to the metabolism and elimination of TZX in humans. This study presents the relevant and novel-appreciative report on TZX metabolism catalyzed by UGT enzymes, which may aid in the assessment of the antiparasitic, antibacterial, and antiviral activities of NTZ for the treatment of various infections.
[Display omitted]
•TZX glucuronidation abilities in the liver and small intestine differ extensively across species.•TZX glucuronidation activities in the liver microsomes were rats > mice ≥ monkeys > dogs > humans.•TZX glucuronidation activities in the intestinal microsomes were mice ≥ rats > monkeys > dogs > humans.•UGT1A1 and/or UGT1A8 mainly contribute to the metabolism and elimination of TZX in humans.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>38889874</pmid><doi>10.1016/j.cbpc.2024.109962</doi></addata></record> |
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| ispartof | Comparative biochemistry and physiology. Toxicology & pharmacology, 2024-09, Vol.283, p.109962, Article 109962 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Animals Antiparasitic Agents - metabolism Dogs Female Glucuronidation Glucuronides - metabolism Glucuronosyltransferase - metabolism Humans Intestinal microsomes Intestine, Small - drug effects Intestine, Small - enzymology Intestine, Small - metabolism Isoenzymes - metabolism Liver - drug effects Liver - enzymology Liver - metabolism Liver microsomes Macaca fascicularis Male Mice Microsomes - enzymology Microsomes - metabolism Microsomes, Liver - metabolism Nitazoxanide (NTZ) Nitro Compounds - metabolism Rats Rats, Sprague-Dawley Species Specificity Thiazoles - metabolism Tizoxanide (TZX) UDP-glucuronosyltransferase (UGT) |
| title | Glucuronidation of tizoxanide, an active metabolite of nitazoxanide, in liver and small intestine: Species differences in humans, monkeys, dogs, rats, and mice and responsible UDP-glucuronosyltransferase isoforms in humans |
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