DISEASE-, NATURAL PRODUCT-, AND DRUG-MEDIATED PHARMACOKINETIC INTERACTIONS OF HEPATIC ORGANIC ANION TRANSPORTING POLYPEPTIDES 1B1 AND 1B3 USING TRANSGENIC HUMANIZED OATP1B MICE

Baron J. Bechtold

doi:10.7273/000006473

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1Bs) are a superfamily of transporters encoded by the SLCO gene family. OATP1Bs are located on the basolateral membrane of hepatocytes and responsible for the hepatic uptake of several amphiphilic molecules, some of which have narrow therapeutic windows. These transporters have been implicated in pharmacokinetic interactions and are specifically noted by the United States Food and Drug Administration as being of particular importance regarding their contribution to potential transporter-mediated drug interactions. Several factors can play a role in the modulation of OATP1B function including polypharmacy, pharmacogenetics, disease, and natural product consumption. The data presented here characterizes drug-drug, natural product-drug, and disease-drug interactions, as well as a multi-factorial disease-natural product-drug interaction. Unfortunately, rodent models express a single ortholog to human OATP1B1 and OATP1B3, known as Oatp1b2, which limits direct clinical translation of pharmacokinetic data. A transgenic humanized mouse strain comprising a knockout of the rodent Slco1a/b gene cluster and insertion of human SLCO1B1 and SLCO1B3 was created, however minimal published pharmacokinetic data are available. The research herein seeks to characterize and explore both single and multi-factorial pharmacokinetic interactions in the humanized OATP1B mice.Chapter two explores drug-drug and natural product-drug interactions of rifampin and silymarin, respectively. Rifampin is a canonical OATP1B inhibitor, and silymarin is an extract from milk thistle seeds that contains known OATP1B inhibitors. Two exogenous probe substrates and two endogenous biomarkers of OATP1B function were used in male humanized OATP1B mice and their FVB wild-type counterparts. Rifampin increased plasma concentrations of all OATP1B substrates and in both strains, with the exception of coproporphyrin-I in FVB mice. Silymarin alone, however, did not precipitate any changes in substrate exposure. Quantification of the silymarin flavonolignan plasma concentrations in the humanized OATP1B mice showed Cmax values at, or slightly below, previously published IC50 values for OATP1B1 and OATP1B3. Chapter three characterizes the effects of different models of nonalcoholic fatty liver disease (NAFLD). Three diets and one drug-induced model was used in male and female humanized OATP1B mice. The diets had minimal effects on SLCO1B1 and SLCO1B3 mRNA expression and OATP1B3 protein expression, and the only pharmacokinetic changes were observed in female mice fed a high fat-high fructose diet. The drug-induced model, tunicamycin, likewise did not cause changes in mRNA expression, but dramatically decreased OATP1B3 expression, leading to a large pharmacokinetic interaction. Chapter three also explored the multi-factorial disease-natural product-drug interaction between NAFLD and silymarin on OATP1B-mediated pharmacokinetics. Here, the disease and silymarin factors alone failed to precipitate a pharmacokinetic interaction, but together caused a larger combined effect. Notably, female OATP1B mice appeared to be a more sensitive model than males. The data presented herein demonstrates strengths and limitations of the humanized OATP1B mice for transporter-mediated pharmacokinetic interaction research. It also forms the basis and justification for future clinical studies of NAFLD and silymarin multi-factorial pharmacokinetic interaction research. Such data will provide information for clinicians to properly counsel patients and improve overall patient outcomes.

DISEASE-, NATURAL PRODUCT-, AND DRUG-MEDIATED PHARMACOKINETIC INTERACTIONS OF HEPATIC ORGANIC ANION TRANSPORTING POLYPEPTIDES 1B1 AND 1B3 USING TRANSGENIC HUMANIZED OATP1B MICE

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