Organic anion-transporting polypeptides (OATP) transporter function, which mediates many drugs' liver uptake, was investigated as a molecular determinant of pharmacokinetic variability. Whole-body PET imaging using ¹¹C-glyburide, a metabolically stable OATP probe, was performed in 16 healthy humans. Ten subjects underwent another ¹¹C-glyburide PET acquisition after OATP inhibition using rifampicin. Subjects were sorted according to age and sex: males<30y (24.0 ± 3.2 y, n = 7), males>50y (57.5 ± 5.6 y, n = 4), and females>50y (60.6 ± 2.4 y, n = 5). The blood-to-liver transfer rate (k _uptake) was estimated to describe OATP function. Rifampicin decreased k _uptake (-73 ± 13%, P < 0.001) and liver exposure (-50 ± 10%, P < 0.001) while increasing exposure in blood (+24 ± 24%, P < 0.01), myocardium, spleen, and brain (P < 0.05). No evidence of extra-hepatic rifampicin-inhibitable transport of ¹¹C-glyburide was found. Baseline liver exposure was 42.6 ± 18.4% higher (P < 0.05) in females>50y compared with males>50 y, consistent with higher k _uptake values (P < 0.05), with negligible impact on blood exposure (P < 0.05). In males, neither liver exposure, blood exposure, nor k _uptake were affected by aging (P < 0.05). k _uptake was positively and negatively correlated with liver (P < 0.01, R ² = 0.78) and blood (P < 0.01, R ² = 0.40) exposures respectively. The impact of OATP function (k _uptake) on liver exposure was 4-fold more pronounced than on blood exposure. OATP function may thus drive important sex-related differences in liver exposure, which were not discernible through conventional blood-based pharmacokinetics.

The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters. Non-alcoholic steatohepatitis (NASH) causes disease-specific alterations to the absorption, distribution, metabolism, and excretion (ADME) processes, including a decrease in protein expression of basolateral uptake transporters, an increase in efflux transporters, and modifications to enzyme activity. This can result in increased drug exposure and adverse drug reactions (ADRs). Our goal was to predict drugs that pose increased risks for ADRs in NASH patients. Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease, mainly non-alcoholic fatty liver disease (NAFLD), 54 of which are known substrates of transporters and/or metabolizing enzymes. Since NASH is the progressive form of NAFLD but is most frequently undiagnosed, we identified other drugs at risk based on NASH-specific alterations to ADME processes. Here, we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH, based on their transport and/or metabolism processes. It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients, especially when eliminated through multiple pathways altered by the disease. Therefore, these results may inform clinicians regarding the selection of drugs for use in NASH patients.