Journal article
Rifampin- and Silymarin-Mediated Pharmacokinetic Interactions of Exogenous and Endogenous Substrates in a Transgenic OATP1B Mouse Model
Molecular pharmaceutics, Vol.21(5), pp.2284-2297
05/06/2024
PMID: 38529622
Abstract
Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCO gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1b gene cluster knockout and human SLCO1B1 and SLCO1B3 gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [Silybum marianum]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC(0-24h) only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC50 values for the relevant OATPs/Oatps. Silymarin increased the C-max of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.
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- Title
- Rifampin- and Silymarin-Mediated Pharmacokinetic Interactions of Exogenous and Endogenous Substrates in a Transgenic OATP1B Mouse Model
- 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, Spokane, WA 99202 USATyler 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
- Molecular pharmaceutics, Vol.21(5), pp.2284-2297
- Academic Unit
- Department of Pharmaceutical Sciences
- Publisher
- Amer Chemical Soc
- Number of pages
- 14
- Grant note
- R56 AT010650 / , National Center for Complementary and Integrative Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Complementary & Alternative Medicine (NCCAM) National Institutes of Health National Center for Complementary and Integrative Health
- Identifiers
- 99901181237101842
- Language
- English
- Resource Type
- Journal article