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Pharmaceutics 2018, 10(3), 125;

In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats

Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center (BBRC), Syngene International Ltd., Bangalore 560100, India
Department of drug metabolism, Gilead Sciences Inc., Foster City, CA 94404, USA
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, 3551 Lawrenceville Road, Princeton, NJ 08540, USA
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 29 June 2018 / Revised: 30 July 2018 / Accepted: 31 July 2018 / Published: 8 August 2018
(This article belongs to the Special Issue ABC Transporter-Mediated Drug Disposition)
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Previously we reported that coproporphyrin-I (CP-I) is an optimal probe substrate for multidrug resistance-associated protein 2 (MRP2), and stimulation of MRP2-mediated transport is probe substrate-dependent. In the present investigation, we assessed if the in vitro stimulation is physiologically relevant. Similar to human MRP2 transport, CP-I was transported by rat Mrp2 in a typical Michaelis-Menten kinetics with apparent Km and Vmax values of 15 ± 6 µM and 161 ± 20 pmol/min/mg protein, respectively. In vivo Mrp2 functions were monitored by biliary and renal secretion of CP-I and its isomer CP-III, in bile-duct cannulated rats before and after treatment with mitoxantrone, progesterone, and verapamil. These compounds stimulated Mrp2-mediated CP-I transport in vitro. No significant increase in biliary or renal clearances, as well as in the cumulative amount of CP-I or CP-III eliminated in bile, were detected following treatment with the in vitro stimulators, indicating an in vitro to in vivo disconnect. In presence of 10 µM bilirubin, the in vitro stimulation was suppressed. We concluded that the in vitro stimulation of CP-I transport mediated by Mrp2 is not translatable in vivo, and proposed that the presence of endogenous compounds such as bilirubin in the liver may contribute to the in vitro to in vivo disconnect. View Full-Text
Keywords: ABCC2; MRP2; in vitro stimulation; drug transporter; coproporphyrin ABCC2; MRP2; in vitro stimulation; drug transporter; coproporphyrin

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Gilibili, R.R.; Kurawattimath, V.; Murali, B.V.; Lai, Y.; Mariappan, T.T.; Shen, H.; Chatterjee, S. In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats. Pharmaceutics 2018, 10, 125.

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