Detection of Weak Organic Anion-Transporting Polypeptide 1B Inhibition by Probenecid with Plasma-Based Coproporphyrin in Humans
| Autor: | Hamza Kandoussi, T. Thanga Mariappan, Jianing Zeng, Vinay K. Holenarsipur, Yueping Zhang, Michael Sinz, Hong Shen |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Coproporphyrins Organic anion transporter 1 Pharmaceutical Science Administration Oral Endogeny Pharmacology 030226 pharmacology & pharmacy 03 medical and health sciences Inhibitory Concentration 50 Solute Carrier Organic Anion Transporter Family Member 1B3 0302 clinical medicine Oral administration In vivo Furosemide medicine Humans Drug Interactions biology Chemistry Liver-Specific Organic Anion Transporter 1 Probenecid Transporter In vitro Healthy Volunteers Organic anion-transporting polypeptide HEK293 Cells 030220 oncology & carcinogenesis Area Under Curve biology.protein Hepatocytes Female medicine.drug |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 48(10) |
| ISSN: | 1521-009X |
| Popis: | 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 1,000 mg PROB alone and in combination with furosemide (FSM), AUC(0-24h) values were 1.39 {plus minus} 0.21- and 1.57 {plus minus} 0.41-fold higher than predose levels for CPI and 1.34 {plus minus} 0.16- and 1.45 {plus minus} 0.57-fold higher for CPIII. Despite increased systemic exposures, no decreases in CPI and CPIII renal clearance (CLR) were observed (0.97 {plus minus} 0.38- and 1.16 {plus minus} 0.51-fold for CPI, and 1.34 {plus minus} 0.53- and 1.50 {plus minus} 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 and 76.0 µM, respectively, in transporter overexpressing cell assay. The inhibition potential was further confirmed by CPI and CPIII hepatocyte uptake experiments. Taken together, these findings indicate that PROB displays weak OATP1B inhibitory effects in vivo and CP is a sensitive endogenous probe of OATP1B inhibition. This study provides an explanation for the heretofore unknown mechanism responsible for PROB9s interactions. 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 DDI, providing explanation for the heretofore unknown mechanism responsible for PROB9s inhibition. It provides evidence to strengthen the claim that CP is a sensitive circulating endogenous biomarker of OATP1B inhibition. |
| Databáze: | OpenAIRE |
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