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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.
- Source :
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Comparative biochemistry and physiology. Toxicology & pharmacology : CBP [Comp Biochem Physiol C Toxicol Pharmacol] 2024 Sep; Vol. 283, pp. 109962. Date of Electronic Publication: 2024 Jun 16. - Publication Year :
- 2024
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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 (CL <subscript>int</subscript> ). Rats and mice exhibited the highest CL <subscript>int</subscript> 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Humans
Dogs
Mice
Rats
Male
Macaca fascicularis
Microsomes, Liver metabolism
Antiparasitic Agents metabolism
Female
Microsomes metabolism
Microsomes enzymology
Rats, Sprague-Dawley
Isoenzymes metabolism
Glucuronosyltransferase metabolism
Thiazoles metabolism
Intestine, Small metabolism
Intestine, Small enzymology
Intestine, Small drug effects
Nitro Compounds metabolism
Liver metabolism
Liver enzymology
Liver drug effects
Species Specificity
Glucuronides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1532-0456
- Volume :
- 283
- Database :
- MEDLINE
- Journal :
- Comparative biochemistry and physiology. Toxicology & pharmacology : CBP
- Publication Type :
- Academic Journal
- Accession number :
- 38889874
- Full Text :
- https://doi.org/10.1016/j.cbpc.2024.109962