1 research outputs found
Role of Hepatic Organic Anion Transporter 2 in the Pharmacokinetics of <i>R</i>- and <i>S</i>‑Warfarin: In Vitro Studies and Mechanistic Evaluation
Interindividual
variability in warfarin dose requirement demands personalized medicine
approaches to balance its therapeutic benefits (anticoagulation) and
bleeding risk. Cytochrome P450 2C9 (<i>CYP2C9</i>) genotype-guided
warfarin dosing is recommended in the clinic, given the more potent <i>S</i>-warfarin is primarily metabolized by CYP2C9. However,
only about 20–30% of interpatient variability in <i>S</i>-warfarin clearance is associated with <i>CYP2C9</i> genotype.
We evaluated the role of hepatic uptake in the clearance of <i>R</i>- and <i>S</i>-warfarin. Using stably transfected
HEK293 cells, both enantiomers were found to be substrates of organic
anion transporter (OAT)2 with a Michaelis–Menten constant (<i>K</i><sub>m</sub>) of ∼7–12 μM but did not
show substrate affinity for other major hepatic uptake transporters.
Uptake of both enantiomers by primary human hepatocytes was saturable
(<i>K</i><sub>m</sub> ≈ 7–10 μM) and
inhibitable by OAT2 inhibitors (e.g., ketoprofen) but not by OATP1B1/1B3
inhibitors (e.g., cyclosporine). To further evaluate the potential
role of hepatic uptake in <i>R</i>- and <i>S</i>-warfarin pharmacokinetics, mechanistic modeling and simulations
were conducted. A “bottom-up” PBPK model, developed
assuming that OAT2–CYPs interplay, well recovered clinical
pharmacokinetics, drug–drug interactions, and <i>CYP2C9</i> pharmacogenomics of <i>R</i>- and <i>S</i>-warfarin.
Clinical data were not available to directly verify the impact of
OAT2 modulation on warfarin pharmacokinetics; however, the bottom-up
PBPK model simulations suggested a proportional change in clearance
of both warfarin enantiomers with inhibition of OAT2 activity. These
results suggest that variable hepatic OAT2 function, in conjunction
with CYP2C, may contribute to the high population variability in warfarin
pharmacokinetics and possibly anticoagulation end points and thus
warrant further clinical investigation