Hepatocyte hopping is the hepatocyte-to-sinusoid-to-hepatocyte shuttling that increases the efficiency of hepatic elimination of xenobiotics. This phenomenon is mediated via efflux of hepatic metabolites by Mrp3 and reuptake by Oatp transporters in sequential hepatocytes until eventual biliary efflux by Mrp2. Sorafenib-glucuronide (SFB-G), the major metabolite of sorafenib (SFB), undergoes hepatocyte hopping, leading to efficient biliary elimination. Nonalcoholic steatohepatitis (NASH) alters the functioning of transporters involved in hepatocyte hopping. The purpose of this study was to quantify the effect of NASH on the three drug disposition processes of hepatocyte hopping. Male FVB and C57BL/6 wild-type (WT), Oatp1a/1b cluster knockout (O^-/-), and Mrp2 knockout (Mrp2 ^-/-) mice were fed a methionine and choline deficient (MCD) diet to induce NASH. Mice were administered 10 mg/kg SFB via oral gavage and concentrations of SFB and SFB-G in plasma quantified using liquid-chromatography tandem mass spectrometry. Compared to WT, plasma area under the concentration-time curve (AUC) of SFB-G increased by 108-fold in the O^-/--C group and by 345-fold in the Mrp2 ^-/--C group. In the WT-NASH group, up-regulation of Mrp3 and decreased Mrp2 function, along with reduced Oatp uptake, elevated SFB-G AUC by 165-fold. SFB-G AUC in the O^-/--NASH group increased by 108-fold compared to WT-C (3.2-fold compared to O^-/--C). SFB-G AUC in the Mrp2 ^-/--NASH group increased by 450-fold (1.2-fold compared to Mrp2^-/--C). Taken together, the mislocalization of Mrp2 in NASH is a major contributor to the decrease in SFB-G biliary efflux, but decreased Oatp uptake and enhanced sinusoidal efflux also limit the contribution of downstream hepatocytes, resulting in plasma retention that recapitulates the altered pharmacokinetics observed in human NASH.

Several patient groups, particularly those with chronic illnesses such as cancer, cardio?vascular disease, hepatitis C, and HIV/AIDS, often supplement their pharmacotherapeutic regimens with botanical natural products (NPs), raising concern for adverse NP-drug interactions. Like drug-drug interactions, common mechanisms underlying pharmacokinetic NP-drug interactions include induction and inhibition of drug metabolizing enzymes and transporters, leading toaltered systemic drug concen?trations and potentially, suboptimal therapeutic effects. However, unlike for drug-drug interactions, rigorous guidelines for assessing the risk of NP-drug interactions are non-existent. Establishing such guidelines for NP-drug interactions poses challenges beyond those for drug-drug interactions because NPs are inherently complex mixtures that vary substantially in phytochemical composition. The National Center for Complementary and Integrative Health created the Center of Excellence for Natural Product-Drug Interaction (NaPDI) Research in September, 2015. The mission of the NaPDI Center is to provide leadership in the identification, evaluation, and dissemination of potential clinically significant pharmaco?kinetic NP-drug interactions. A key deliverable of the Center is a set of Recommended Approaches to guide researchers in the proper conduct of NP- drug interaction studies. These approaches will be based on results generated from a series of Interaction Projects that will examine four methodically selected NPs as precipitants of metabolism- and/or transporter-mediated interactions with clinically relevant object drugs. Three of these NPs- green tea, goldenseal, and cannabinoids- have been advanced to Interaction Projects that include human mechanistic in vitro studies, physiologically-based pharmacoki?netic modeling and simulation, and clinical studies. Key data generated from the Interaction Projects are being entered into a data repository, which will be disseminated to researchers via a public access portal. Collectively, the efforts of the NaPDI Center should lead to improved design of future NP-drug interaction research and ultimately, improved decisions on the optimal management of clinically relevant interactions.