In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats
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 re...
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MDPI AG
2018-08-01
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| Series: | Pharmaceutics |
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| Online Access: | http://www.mdpi.com/1999-4923/10/3/125 |
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| author | Ravindranath Reddy Gilibili Vishwanath Kurawattimath Bokka Venkata Murali Yurong Lai T. Thanga Mariappan Hong Shen Sagnik Chatterjee |
| author_facet | Ravindranath Reddy Gilibili Vishwanath Kurawattimath Bokka Venkata Murali Yurong Lai T. Thanga Mariappan Hong Shen Sagnik Chatterjee |
| author_sort | Ravindranath Reddy Gilibili |
| collection | DOAJ |
| description | 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. |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-11T12:19:14Z |
| publishDate | 2018-08-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj.art-5d255df6613d4527909558d783ee0cbd2022-12-22T04:24:10ZengMDPI AGPharmaceutics1999-49232018-08-0110312510.3390/pharmaceutics10030125pharmaceutics10030125In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in RatsRavindranath Reddy Gilibili0Vishwanath Kurawattimath1Bokka Venkata Murali2Yurong Lai3T. Thanga Mariappan4Hong Shen5Sagnik Chatterjee6Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center (BBRC), Syngene International Ltd., Bangalore 560100, IndiaPharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center (BBRC), Syngene International Ltd., Bangalore 560100, IndiaPharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center (BBRC), Syngene International Ltd., Bangalore 560100, IndiaDepartment of drug metabolism, Gilead Sciences Inc., Foster City, CA 94404, USAPharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center (BBRC), Syngene International Ltd., Bangalore 560100, IndiaPharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, 3551 Lawrenceville Road, Princeton, NJ 08540, USAPharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb R&D Center (BBRC), Syngene International Ltd., Bangalore 560100, IndiaPreviously 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.http://www.mdpi.com/1999-4923/10/3/125ABCC2MRP2in vitro stimulationdrug transportercoproporphyrin |
| spellingShingle | Ravindranath Reddy Gilibili Vishwanath Kurawattimath Bokka Venkata Murali Yurong Lai T. Thanga Mariappan Hong Shen Sagnik Chatterjee In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats Pharmaceutics ABCC2 MRP2 in vitro stimulation drug transporter coproporphyrin |
| title | In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats |
| title_full | In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats |
| title_fullStr | In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats |
| title_full_unstemmed | In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats |
| title_short | In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats |
| title_sort | in vitro stimulation of multidrug resistance associated protein 2 function is not reproduced in vivo in rats |
| topic | ABCC2 MRP2 in vitro stimulation drug transporter coproporphyrin |
| url | http://www.mdpi.com/1999-4923/10/3/125 |
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