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J Pharm Sci. 2017 Sep;106(9):2704-2714. doi: 10.1016/j.xphs.2017.04.052. Epub 2017 Apr 30.

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

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Pharmacokinetic Research Laboratories, Ono Pharmaceutical Company, Ltd., Ibaraki, Japan.
Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Kanagawa, Japan.
Oncology Clinical Development Planning, Ono Pharmaceutical Company, Ltd., Osaka, Japan.
Translational Medicine Center, Ono Pharmaceutical Company, Ltd., Osaka, Japan.
Pharmacokinetic Research Laboratories, Ono Pharmaceutical Company, Ltd., Ibaraki, Japan. Electronic address:


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 Km 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 Km and Vmax decreased with increased HSA concentration. A greater decrease in unbound Km than in Vmax resulted in increased uptake clearance (Vmax/unbound Km) with increased HSA concentration, the so-called albumin-mediated uptake. At 2% HSA concentration, unbound Km was 0.00657 μmol/L. A physiologically based PK model assuming saturable hepatic uptake nearly replicated clinical PK of compound A. Unbound Km for hepatic uptake estimated from the model was 0.000767 μmol/L, lower than the in vitro unbound Km at 2% HSA concentration, whereas decreased Km with increased concentration of HSA in vitro indicated lower Km at physiological HSA concentration (4%-5%). In addition, unbound Km values for metabolizing enzymes were much higher than unbound Km for OATP1B3, indicating that the nonlinear PK of compound A is primarily attributed to saturated OATP1B3-mediated hepatic uptake of compound A.


ADME; albumin; clinical pharmacokinetics; food effects; hepatic transport; mathematical model; nonlinear pharmacokinetics; organic anion–transporting polypeptide transporters; pharmacokinetics; protein binding

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