Analysis of Nonlinear Pharmacokinetics of a Highly Albumin-Bound Compound: Contribution of Albumin-Mediated Hepatic Uptake Mechanism.

The cause of nonlinear pharmacokinetics (PK) (more than dose-proportional increase in exposure) of a urea derivative under development (compound A: anionic compound [pKa: 4.4]; LogP: 6.5; and plasma protein binding: 99.95%) observed in a clinical trial was investigated. Compound A was metabolized by CYP3A4, UGT1A1, and UGT1A3 with unbound K of 3.3-17.8 μmol/L. OATP1B3-mediated uptake of compound A determined in the presence of human serum albumin (HSA) showed that unbound K and V decreased with increased HSA concentration. A greater decrease in unbound K than in V resulted in increased uptake clearance (V/unbound K) with increased HSA concentration, the so-called albumin-mediated uptake. At 2% HSA concentration, unbound K was 0.00657 μmol/L. A physiologically based PK model assuming saturable hepatic uptake nearly replicated clinical PK of compound A. Unbound K for hepatic uptake estimated from the model was 0.000767 μmol/L, lower than the in vitro unbound K at 2% HSA concentration, whereas decreased K with increased concentration of HSA in vitro indicated lower K at physiological HSA concentration (4%-5%). In addition, unbound K values for metabolizing enzymes were much higher than unbound K for OATP1B3, indicating that the nonlinear PK of compound A is primarily attributed to saturated OATP1B3-mediated hepatic uptake of compound A.