Hepatic OATP1B zonal distribution: Implications for rifampicin-mediated drug-drug interactions explored within a PBPK framework.

OATP1B facilitates the uptake of xenobiotics into hepatocytes and is a prominent target for drug-drug interactions (DDIs). Reduced systemic exposure of OATP1B substrates has been reported following multiple-dose rifampicin; one explanation for this observation is OATP1B induction. Non-uniform hepatic distribution of OATP1B may impact local rifampicin tissue concentrations and rifampicin-mediated protein induction, which may affect the accuracy of transporter- and/or metabolizing enzyme-mediated DDI predictions. We incorporated quantitative zonal OATP1B distribution data from immunofluorescence imaging into a PBPK modeling framework to explore rifampicin interactions with OATP1B and CYP substrates. PBPK models were developed for rifampicin, two OATP1B substrates, pravastatin and repaglinide (also metabolized by CYP2C8/CYP3A4), and the CYP3A probe, midazolam. Simulated hepatic uptake of pravastatin and repaglinide increased from the periportal to the pericentral region (approximately 2.1-fold), consistent with OATP1B distribution data. Simulated rifampicin unbound intracellular concentrations increased in the pericentral region (1.64-fold) compared to simulations with uniformly distributed OATP1B. The absolute average fold error of the rifampicin PBPK model for predicting substrate maximal concentration (Cmax) and area under the plasma concentration-time curve (AUC) ratios was 1.41 and 1.54, respectively (nine studies). In conclusion, hepatic OATP1B distribution has a considerable impact on simulated zonal substrate uptake clearance values and simulated intracellular perpetrator concentrations, which regulate transporter and metabolic DDIs. Additionally, accounting for rifampicin-mediated OATP1B induction in parallel with inhibition improved model predictions. This study provides novel insight into the effect of hepatic OATP1B distribution on site-specific DDI predictions and the impact of accounting for zonal transporter distributions within PBPK models.

Effects of PFAS on human liver transporters: implications for health outcomes.

Per- and polyfluoroalkyl substances (PFAS) have become internationally recognized over the past three decades as persistent organic pollutants used in the production of various consumer and industrial goods. Research efforts continue to gauge the risk that historically used, and newly produced, PFAS may cause to human health. Numerous studies report toxic effects of PFAS on the human liver as well as increased serum cholesterol levels in adults. A major concern with PFAS, also dubbed "forever chemicals," is that they accumulate in the liver and kidney and persist in serum. The mechanisms responsible for their disposition and excretion in humans are poorly understood. A better understanding of the interaction of PFAS with liver transporters, as it pertains to the disposition of PFAS and other xenobiotics, could provide mechanistic insight into human health effects and guide efforts toward risk assessment of compounds in development. This review summarizes the current state of the literature on the emerging relationships (eg, substrates, inhibitors, modulators of gene expression) between PFAS and specific hepatic transporters. The adaptive and toxicological responses of hepatocytes to PFAS that reveal linkages to pathologies and epidemiological findings are highlighted. The evidence suggests that our understanding of the molecular landscape of PFAS must improve to determine their impact on the expression and function of hepatocyte transporters that play a key role in PFAS or other xenobiotic disposition. From here, we can assess what role these changes may have in documented human health outcomes.

Alterations in zonal distribution and plasma membrane localization of hepatocyte bile acid transporters in patients with NAFLD.

BACKGROUND: NAFLD is highly prevalent with limited treatment options. Bile acids (BAs) increase in the systemic circulation and liver during NAFLD progression. Changes in plasma membrane localization and zonal distribution of BA transporters can influence transport function and BA homeostasis. However, a thorough characterization of how NAFLD influences these factors is currently lacking. This study aimed to evaluate the impact of NAFLD and the accompanying histologic features on the functional capacity of key hepatocyte BA transporters across zonal regions in human liver biopsies. METHODS: A novel machine learning image classification approach was used to quantify relative zonal abundance and plasma membrane localization of BA transporters (bile salt export pump [BSEP], sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide [OATP] 1B1 and OATP1B3) in non-diseased (n = 10), NAFL (n = 9), and NASH (n = 11) liver biopsies. Based on these data, membrane-localized zonal abundance (MZA) measures were developed to estimate transporter functional capacity. RESULTS: NAFLD diagnosis and histologic scoring were associated with changes in transporter membrane localization and zonation. Increased periportal BSEPMZA (mean proportional difference compared to non-diseased liver of 0.090) and decreased pericentral BSEPMZA (-0.065) were observed with NASH and also in biopsies with higher histologic scores. Compared to Non-diseased Liver, periportal OATP1B3MZA was increased in NAFL (0.041) and NASH (0.047). Grade 2 steatosis (mean proportional difference of 0.043 when compared to grade 0) and grade 1 lobular inflammation (0.043) were associated with increased periportal OATP1B3MZA. CONCLUSIONS: These findings provide novel mechanistic insight into specific transporter alterations that impact BA homeostasis in NAFLD. Changes in BSEPMZA likely contribute to altered BA disposition and pericentral microcholestasis previously reported in some patients with NAFLD. BSEPMZA assessment could inform future development and optimization of NASH-related pharmacotherapies.

Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD).

PURPOSE: This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics. METHODS: A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, 11C-metformin, morphine and the glucuronide metabolite of morphine). RESULTS: PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of 11C-metformin were consistent with the clinically-observed data. Importantly, the PBPK simulations using the virtual NAFLD population model provided reliable estimates of the extent of changes in key pharmacokinetic parameters for the exemplar drugs, with mean predicted ratios (NAFLD patients divided by healthy individuals) within 0.80- to 1.25-fold of the clinically-reported values, except for midazolam (prediction-fold difference of 0.72). CONCLUSION: A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population.

Membrane transporters in drug development and as determinants of precision medicine.

The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions.