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Hepatic microsomal UDP-glucuronosyltransferase (UGT) activities in the microminipig

Eriko Higashi1, Akihiro Ando, Shunsuke Iwano

  • 1Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa, 248-8555, Japan.

Biopharmaceutics & Drug Disposition
|April 23, 2014
PubMed

Insights

Microminipigs show distinct UDP-glucuronosyltransferase (UGT) activities, with higher estradiol and morphine glucuronidation than humans, aiding in selecting animal models for drug metabolism studies.

Area of Science:

  • Pharmacology and Toxicology
  • Drug Metabolism
  • Biochemistry

Background:

  • The microminipig is a novel animal model for nonclinical studies.
  • Understanding species differences in drug metabolism is crucial for interpreting study results.
  • UDP-glucuronosyltransferase (UGT) enzymes play a key role in the metabolism of many compounds.

Purpose of the Study:

  • To characterize hepatic UGT activity in microminipigs.
  • To compare microminipig UGT activity with that of humans and other animal models.
  • To provide data for selecting appropriate animal models in drug development.

Main Methods:

  • In vitro assessment of UGT activity using liver microsomes from microminipigs, humans, mice, rats, dogs, monkeys, and minipigs.
  • Measurement of glucuronidation of specific substrates (estradiol, imipramine, serotonin, propofol, AZT, morphine) using LC-MS/MS.
  • Analysis of UGT isoforms including human UGT1A1, 1A4, 1A6, 1A9, and 2B7.

Main Results:

  • Microminipigs exhibited higher estradiol-3-glucuronidation than humans and other species, particularly at 1 day old.
  • Imipramine-N-glucuronidation, characteristic of human UGT1A4, was observed in microminipigs but not dogs.
  • Morphine-3-glucuronidation was higher in microminipigs than in humans, while AZT-glucuronidation was lower.
  • Overall UGT activity profiles in microminipigs closely resembled those of minipigs.

Conclusions:

  • Microminipig hepatic UGT activity differs from humans, particularly in estradiol and morphine metabolism.
  • The findings highlight the importance of considering species-specific UGT profiles when selecting animal models for drug studies.
  • Microminipigs may serve as a valuable model for specific drug metabolism pathways, similar to minipigs.
Keywords:
UGTglucuronidationmicrominipigspecies differences

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