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Journal article
Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice
Drug metabolism and disposition, Vol.52(6), pp.355-367
05/01/2024
PMID: 38485280
Abstract
Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter (SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathologic and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1 and SLCO1B3. Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1 expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multifactorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55 -fold from the diet alone and the 1.88 -fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multifactorial pharmacokinetic interactions.
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Details
- Title
- Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice
- Creators
- Baron J. Bechtold - Washington State University SpokaneKatherine D. Lynch - Washington State University SpokaneVictoria O. Oyanna - Washington State University SpokaneM. Ridge Call - Washington State Univ, Dept Pharmaceut Sci, Pullman, WA USALaura A. White - Washington State University, Department of Veterinary Microbiology and PathologyTyler N. Graf - University of North Carolina at GreensboroNicholas H. Oberlies - University of North Carolina at GreensboroJohn D. Clarke - Washington State University, Department of Pharmaceutical Sciences
- Publication Details
- Drug metabolism and disposition, Vol.52(6), pp.355-367
- Academic Unit
- Department of Pharmaceutical Sciences
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 13
- Grant note
- R56 AT010650 / National Institutes of Health National Center Complementary and Integrative Health
- Identifiers
- 99901181237201842
- Language
- English
- Resource Type
- Journal article