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Research ArticleArticle

Detection of Weak Organic Anion–Transporting Polypeptide 1B Inhibition by Probenecid with Plasma-Based Coproporphyrin in Humans

Yueping Zhang, Vinay K. Holenarsipur, Hamza Kandoussi, Jianing Zeng, T. Thanga Mariappan, Michael Sinz and Hong Shen
Drug Metabolism and Disposition October 2020, 48 (10) 841-848; DOI: https://doi.org/10.1124/dmd.120.000076
Yueping Zhang
Departments of Metabolism and Pharmacokinetics (Y.Z., M.S., H.S.) and Bioanalytical Sciences (H.K., J.Z.), Bristol Myers Squibb Company, Princeton, New Jersey; and Departments of Metabolism and Pharmacokinetics (V.K.H., T.T.M.), Biocon Bristol Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bommasandra IV Phase, Bangalore, India
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Vinay K. Holenarsipur
Departments of Metabolism and Pharmacokinetics (Y.Z., M.S., H.S.) and Bioanalytical Sciences (H.K., J.Z.), Bristol Myers Squibb Company, Princeton, New Jersey; and Departments of Metabolism and Pharmacokinetics (V.K.H., T.T.M.), Biocon Bristol Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bommasandra IV Phase, Bangalore, India
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Hamza Kandoussi
Departments of Metabolism and Pharmacokinetics (Y.Z., M.S., H.S.) and Bioanalytical Sciences (H.K., J.Z.), Bristol Myers Squibb Company, Princeton, New Jersey; and Departments of Metabolism and Pharmacokinetics (V.K.H., T.T.M.), Biocon Bristol Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bommasandra IV Phase, Bangalore, India
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Jianing Zeng
Departments of Metabolism and Pharmacokinetics (Y.Z., M.S., H.S.) and Bioanalytical Sciences (H.K., J.Z.), Bristol Myers Squibb Company, Princeton, New Jersey; and Departments of Metabolism and Pharmacokinetics (V.K.H., T.T.M.), Biocon Bristol Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bommasandra IV Phase, Bangalore, India
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T. Thanga Mariappan
Departments of Metabolism and Pharmacokinetics (Y.Z., M.S., H.S.) and Bioanalytical Sciences (H.K., J.Z.), Bristol Myers Squibb Company, Princeton, New Jersey; and Departments of Metabolism and Pharmacokinetics (V.K.H., T.T.M.), Biocon Bristol Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bommasandra IV Phase, Bangalore, India
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Michael Sinz
Departments of Metabolism and Pharmacokinetics (Y.Z., M.S., H.S.) and Bioanalytical Sciences (H.K., J.Z.), Bristol Myers Squibb Company, Princeton, New Jersey; and Departments of Metabolism and Pharmacokinetics (V.K.H., T.T.M.), Biocon Bristol Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bommasandra IV Phase, Bangalore, India
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Hong Shen
Departments of Metabolism and Pharmacokinetics (Y.Z., M.S., H.S.) and Bioanalytical Sciences (H.K., J.Z.), Bristol Myers Squibb Company, Princeton, New Jersey; and Departments of Metabolism and Pharmacokinetics (V.K.H., T.T.M.), Biocon Bristol Myers Squibb R&D Centre (BBRC), Syngene International Ltd., Biocon Park, Bommasandra IV Phase, Bangalore, India
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Abstract

Probenecid (PROB) is a clinical probe inhibitor of renal organic anion transporter (OAT) 1 and OAT3 that inhibits in vitro activity of hepatic drug transporters OATP1B1 and OATP1B3. It was hypothesized that PROB could potentially affect the disposition of OATP1B drug substrates. The plasma levels of the OATP1B endogenous biomarker candidates, including coproporphyrin I (CPI), CPIII, hexadecanedioate (HDA), and tetradecanedioate (TDA), were examined in 14 healthy subjects treated with PROB. After oral administration with 1000 mg PROB alone and in combination with furosemide (FSM), AUC(0–24 h) values were 1.39 ± 0.21-fold and 1.57 ± 0.41-fold higher than predose levels for CPI and 1.34 ± 0.16-fold and 1.45 ± 0.57-fold higher for CPIII. Despite increased systemic exposures, no decreases in CPI and CPIII renal clearance were observed (0.97 ± 0.38-fold and 1.16 ± 0.51-fold for CPI, and 1.34 ± 0.53-fold and 1.50 ± 0.69-fold for CPIII, respectively). These results suggest that the increase of CP systemic exposure is caused by OATP1B inhibition. Consistent with this hypothesis, PROB inhibited OATP1B1- and OATP1B3-mediated transport of CPI in a concentration-dependent manner, with IC50 values of 167 ± 42.0 and 76.0 ± 17.2 µM, respectively, in transporter-overexpressing human embryonic kidney cell assay. The inhibition potential was further confirmed by CPI and CPIII hepatocyte uptake experiments. In contrast, administration of PROB alone did not change AUC(0–24 h) of HDA and TDA relative to prestudy levels, although the administration of PROB in combination with FSM increased HDA and TDA levels compared with FSM alone (1.02 ± 0.18-fold and 0.90 ± 0.20-fold vs. 1.71 ± 0.43-fold and 1.62 ± 0.40-fold). Taken together, these findings indicate that PROB displays weak OATP1B inhibitory effects in vivo and that coproporphyrin is a sensitive endogenous probe of OATP1B inhibition. This study provides an explanation for the heretofore unknown mechanism responsible for PROB’s interaction with other xenobiotics.

SIGNIFICANCE STATEMENT This study suggested that PROB is a weak clinical inhibitor of OATP1B based on the totality of evidence from the clinical interaction between PROB and CP and the in vitro inhibitory effect of PROB on OATP1B-mediated CP uptake. It demonstrates a new methodology of utilizing endogenous biomarkers to evaluate complex drug-drug interaction, providing explanation for the heretofore unknown mechanism responsible for PROB’s inhibition. It provides evidence to strengthen the claim that CP is a sensitive circulating endogenous biomarker of OATP1B inhibition.

Footnotes

    • Received April 11, 2020.
    • Accepted July 13, 2020.
  • This study is supported by Bristol Myers Squibb Company.

  • https://doi.org/10.1124/dmd.120.000076.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (10)
Drug Metabolism and Disposition
Vol. 48, Issue 10
1 Oct 2020
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Research ArticleArticle

Use of Coproporphyrin to Detect Weak OATP1B Inhibition by PROB

Yueping Zhang, Vinay K. Holenarsipur, Hamza Kandoussi, Jianing Zeng, T. Thanga Mariappan, Michael Sinz and Hong Shen
Drug Metabolism and Disposition October 1, 2020, 48 (10) 841-848; DOI: https://doi.org/10.1124/dmd.120.000076

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Research ArticleArticle

Use of Coproporphyrin to Detect Weak OATP1B Inhibition by PROB

Yueping Zhang, Vinay K. Holenarsipur, Hamza Kandoussi, Jianing Zeng, T. Thanga Mariappan, Michael Sinz and Hong Shen
Drug Metabolism and Disposition October 1, 2020, 48 (10) 841-848; DOI: https://doi.org/10.1124/dmd.120.000076
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