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A systematic in vitro investigation of the inhibitor preincubation effect on multiple classes of uptake transporters

Tatrai, Peter, Schweigler, Patrick, Poller, Birk, Domange, Norbert, Hanna, Imad, Gaborik, Zsuzsanna and Huth, Felix (2019) A systematic in vitro investigation of the inhibitor preincubation effect on multiple classes of uptake transporters. Drug Metabolism and Disposition. ISSN 1521-009X


Preincubation of a drug uptake transporter with its inhibitor in a cell-based assay may result in the
apparent enhancement of the inhibitory potency. Limited data is available on whether this
potentiation of transporter inhibition by preincubation (PTIP) takes place with clinically relevant
solute-carrier transporters other than OATP1B1/3. Therefore, PTIP was examined systematically
using OATP1B1/3, OAT1/3, OCT1/2, and MATE1/2-K cell lines. IC50 values were determined with
or without 3 hours of preincubation, and compounds with a PTIP ≥2.5x were further characterised
by assessing the time course of transport inhibition potency and cellular concentration. The extent
of potentiation was correlated with the physicochemical properties of individual inhibitors. PTIP
was observed for OCTs as well as OATPs but not for OATs or MATEs, and most instances of
PTIP persisted after controlling for toxicity and non-specific binding. In certain cases,
preincubation in excess of 2 hours was required to attain full inhibitory potency. For 5/30 drugs
examined, preincubation had the potential to change the in vitro drug-drug interaction risk
prediction from ‘no risk’ to ‘risk’ based on current regulatory criteria. Molecular weight and LogD7.4,
as well as the ratio of passive cellular accumulation and cellular uptake rate (Kp,passive/PSinf)
correlated with PTIP; thus, low cellular permeation and a slow build-up of unbound intracellular
inhibitor concentration may contribute to PTIP. Taken together, our data suggest that PTIP is
partly determined by the physicochemical properties of the perpetrator drug, and preincubation
may affect the in vitro predicted DDI risk for OCTs as well as OATPs.

Item Type: Article
Keywords: Transporter, inhibition, preincubation
Date Deposited: 25 May 2019 00:45
Last Modified: 25 May 2019 00:45


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