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

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


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.

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

MeSH terms

  • Adult
  • Biological Availability
  • Biological Transport
  • Computer Simulation
  • Cytochrome P-450 CYP3A / metabolism
  • Female
  • Glucuronosyltransferase / metabolism
  • Humans
  • Liver / metabolism*
  • Male
  • Models, Biological
  • Protein Binding
  • Serum Albumin, Human / metabolism*
  • Urea / analogs & derivatives*
  • Urea / metabolism
  • Urea / pharmacokinetics*


  • Urea
  • Cytochrome P-450 CYP3A
  • UDP-glucuronosyltransferase, UGT1A3
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Serum Albumin, Human