Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition
| Autor: | Vinay K. Holenarsipur, Robert Langish, Jun Dai, Petia Shipkova, Yaofeng Cheng, Nilesh Gaud, Sabariya Selvam, Sandhya Mandlekar, Prabhakar Rajanna, Onkar Date, Senthilkumar Murugesan, Hong Shen, Yurong Lai, Punit Marathe, William G. Humphreys |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male Drug Coproporphyrins media_common.quotation_subject Urinary system Cmax Organic Anion Transporters Endogeny Urine Pharmacology Biology 030226 pharmacology & pharmacy Young Adult 03 medical and health sciences 0302 clinical medicine medicine Humans Drug Interactions Rosuvastatin Rosuvastatin Calcium media_common Middle Aged Organic anion-transporting polypeptide Biochemistry 030220 oncology & carcinogenesis biology.protein Molecular Medicine Rifampin Biomarkers medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 358:397-404 |
| ISSN: | 1521-0103 |
| Popis: | In the present study, an open-label, three-treatment, three-period clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 ± 0.21 and 0.15 ± 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (Cmax) of CP-I and CP-III by 5.7- and 5.4-fold (RIF) or 5.7- and 6.5-fold (RIF+RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC0-24h) of CP-I and CP-III with RIF and RSV increased by 4.0- and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, Cmax and AUC0-24h of RSV increased by 13.2- and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies. |
| Databáze: | OpenAIRE |
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