Estimation of the Effect of OAT2-Mediated Active Uptake on Meloxicam Exposure in the Human Liver.

Active uptake mediated by organic anion transporter 2 (OAT2) has been previously hypothesized as a key player in hepatic disposition of its substrates. Previous studies have shown that another hepatic uptake transporter, organic anion transporting polypeptides (OATP) 1B1, significantly elevates liver concentrations of drugs transported by it. As tissue concentration typically governs pharmacodynamics, drug-drug interactions, and toxicity in the liver, it is important to understand if OAT2 functions similarly to OATP1B1 in raising liver exposure. Since this is a research problem that cannot be easily assessed in clinical studies at this time, here we estimated human liver exposure of an OAT2 substrate meloxicam using a deduction method based on physiologically based pharmacokinetic (PBPK) modeling of clinical systemic exposure data. Although in vitro data suggest that OAT2-mediated active uptake is involved in meloxicam disposition, the modeling result concludes that its unbound liver exposure is unlikely significantly different from its unbound systemic exposure. This conclusion is further supported by data and modeling from a terminal monkey study and in vitro hepatocyte studies with bovine serum albumin. Overall, based on currently available data, we do not expect that OAT2 has a strong impact on the liver exposure of meloxicam.