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

Abstract

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.

The Presence of a Transporter-Induced Protein Binding Shift: A New Explanation for Protein-Facilitated Uptake and Improvement for In Vitro-In Vivo Extrapolation

“…Additional previous support for TIPBS was seen when measuring the uptake of a highly bound new chemical entity, shown to be an OATP1B3 substrate. CL int increased with increased HSA concentration in transfected human embryonic kidney (HEK293) cells, where the mechanisms hypothesized with the hepatocyte cell surface may not be present, but overexpression of the OATP transporter is present (Fukuchi et al, 2017).…”

An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation

“…A facilitated uptake process was seen for both compounds, but there was a more dramatic increase in the unbound uptake for pitavastatin, which has a higher affinity for OATP, than for ANS which has a relatively lower affinity for Oatp. The authors hypothesized, “the higher the affinity for the transporter, the more effective is the albumin-mediated enhancement.” Furthermore, when examining the uptake of highly bound new chemical entity, compound A, which was shown to be an OATP1B3 substrate, the unbound clearance increased with increased HSA concentration in HEK293 cells where the mechanisms hypothesized in hepatocytes may not be present, but overexpression of the OATP transporters is (Fukuchi et al, 2017). Ongoing work in our laboratory will continue to test to validity of this hypothesis.…”

Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule–Related Therapeutic Modalities

“…1 in the presence of plasma or albumin. In another study, it was shown that increased hepatic uptake clearance (V max /unbound K m ) was observed with increasing albumin concentrations, and this phenomenon was explained by albumin-facilitated uptake (Fukuchi et al, 2017). Although a substantial amount of data have been presented that seems to support this albumin-facilitated uptake hypothesis (Bowman and Benet, 2018), there is still a lot of speculation about the exact mechanism; several hypotheses have been proposed (Poulin et al, 2016;Bowman and Benet, 2018), including the following:…”