دورية أكاديمية
A systematic in vitro investigation of the inhibitor preincubation effect on multiple classes of uptake transporters
| العنوان: | A systematic in vitro investigation of the inhibitor preincubation effect on multiple classes of uptake transporters |
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| المؤلفون: | Tatrai, Peter, Schweigler, Patrick, Poller, Birk, Domange, Norbert, Hanna, Imad, Gaborik, Zsuzsanna, Huth, Felix |
| بيانات النشر: | ASPET |
| سنة النشر: | 2019 |
| المجموعة: | The Novartis Repository (Novartis, Switzerland) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| العلاقة: | 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 |
| الإتاحة: | https://oak.novartis.com/38589Test/ https://www.ncbi.nlm.nih.gov/pubmed/31068368Test |
| رقم الانضمام: | edsbas.6A724C6B |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |