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Clinically Relevant OATP2B1 Inhibitors in Marketed Drug Space
journal contribution
posted on 2020-01-01, 12:33 authored by Melissa
S. Unger, Jennypher Mudunuru, Matthias Schwab, Carsten Hopf, Gerard Drewes, Anne T. Nies, Maciej J. Zamek-Gliszczynski, Friedrich B. M. ReinhardOATP2B1 is an intestinal and hepatic drug uptake transporter.
Intestinal
OATP2B1 has been elucidated as the mechanism of unexpected clinical
drug–drug interactions (DDIs), where drug exposure was unexpectedly
decreased with unchanged half-life. Hepatic OATP2B1 may be an understudied
clinical DDI mechanism. The aim of the present work was to understand
the prevalence of clinically relevant intestinal and hepatic OATP2B1
inhibitors in marketed drug space. HEK293 cells stably overexpressing
human OATP2B1 or vector control were generated and cultured for 72
h in a 96-well format. OATP2B1-mediated uptake of dibromofluorescein
(DBF) was found to be optimal at 10 μM concentration and 30
min incubation time. A total of 294 drugs (top 300 marketed drugs,
excluding biologics and restricted drugs, supplemented with ∼100
small-molecule drugs) were screened for OATP2B1 inhibition at 10 μM.
Drugs demonstrating ≥50% inhibition in this screen were advanced
for IC50 determination, which was extrapolated to clinical
intestinal and hepatic OATP2B1 inhibition as per 2017 FDA DDI guidance.
Of the 294 drugs screened, 67 elicited ≥50% inhibition of OATP2B1-mediated
DBF uptake at 10 μM screening concentration. For the 67 drugs
flagged in the single-concentration inhibition screen, upon evaluation
of a full concentration range, IC50 values could be determined
for 58 drugs. OATP2B1 IC50 values established for these
58 drugs were extrapolated as potentially clinically relevant at the
intestinal level for 38 orally administered drugs (Igut/IC50 ≥ 10), and 17 were flagged
as potential clinical inhibitors of hepatic OATP2B1 uptake (1 + Iin,max,u/IC50 ≥ 1.1). This
analysis of 294 drugs demonstrated prevalence of clinically relevant
intestinal and hepatic OATP2B1 inhibitors to be 13 and 6%, respectively.
As OATP2B1-inhibitor drugs are not exceedingly rare, these results
suggest that clinical OATP2B1 DDIs have been rarely observed because
OATP2B1 is uncommonly the predominant determinant of drug disposition.
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Keywords
single-concentration inhibition screen294 drugsOATP 2B IC 50 values10 μ MIC 50 determinationhepatic OATP 2B inhibitorsHEK 293 cells stably overexpressingOATP 2B10 μ M screening concentrationIC 50 valuesOATP 2B DDIsDrug Space OATP 2Bhepatic drug uptake transporterOATP 2B inhibitionIntestinal OATP 2BOATP 2B drugs10 μ M concentrationOATP 2B uptakeOATP 2B Inhibitors58 drugsHepatic OATP 2BOATP 2B DBF uptake30 min incubation time2017 FDA DDI guidancehepatic OATP 2B inhibition
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