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Glucuronidation, a pivotal phase II biotransformation process, involves the coupling of glucuronic acid to a drug or xenobiotic. Given its widespread occurrence and critical role in drug metabolism, it's considered the most crucial phase II reaction. It enhances the water solubility of substances, aiding their expulsion from the body. The driving force behind these reactions is a group of enzymes known as UDP-glucuronosyltransferases (UGTs). UGTs facilitate the transfer of a glucuronic acid...
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Phase II reactions are essential for the detoxification and elimination of drugs from the body. These reactions involve the conjugation of parent drugs or their phase I metabolites with endogenous molecules, resulting in more hydrophilic drug conjugates. The primary conjugation reactions in this phase are sulfation and glucuronidation. Both sulfation and glucuronidation typically produce biologically inactive metabolites. However, in some cases involving prodrugs, active metabolites may be...
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Species and tissue differences in regorafenib glucuronidation.

Ayaka Kojima1, Masayuki Nadai1, Miki Katoh1

  • 1Department of Pharmaceutics, Faculty of Pharmacy, Meijo University, Nagoya, Japan.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|March 21, 2022
PubMed
Summary

Regorafenib glucuronidation varies by species and tissue, primarily involving uridine 5'-diphosphate glucuronosyltransferase (UGT) 1A9. Differences in UGT1A9 expression impact regorafenib metabolism across liver and kidney tissues.

Keywords:
Regorafenibglucuronidationkinetic analysisspecies differencestissue differences

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Area of Science:

  • Pharmacokinetics
  • Drug Metabolism
  • Comparative Physiology

Background:

  • Regorafenib is primarily metabolized via glucuronidation by uridine 5'-diphosphate glucuronosyltransferase (UGT) 1A9 in humans.
  • UGT1A9 and its orthologues are expressed in key metabolic tissues like the liver, small intestine, and kidney.

Purpose of the Study:

  • To investigate and elucidate species and tissue-specific differences in regorafenib glucuronidation.
  • To compare regorafenib metabolism in hepatic and extrahepatic tissues across humans and various animal models.

Main Methods:

  • Regorafenib glucuronidation kinetics were analyzed using the Michaelis-Menten model.
  • Studies were conducted on liver, kidney, and small intestine tissues from humans, monkeys, and mice.
  • Rat UGT1A9 was identified as a pseudogene, precluding its involvement in glucuronidation.

Main Results:

  • Hepatic glucuronidation followed monophasic kinetics in humans, monkeys, and mice, but was undetectable in rats.
  • Maximum velocity (Vmax) for hepatic glucuronidation was highest in monkeys, followed by humans and mice.
  • Kidney exhibited higher Vmax than liver in humans and monkeys; mouse kidneys showed no detectable glucuronidation.

Conclusions:

  • Species and tissue variations in regorafenib glucuronidation are significant.
  • UGT1A9 expression levels are a key determinant of regorafenib glucuronidation.
  • Extrahepatic tissues, particularly the kidney, play a role in regorafenib metabolism, with notable species-specific differences.