Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

• Published in: Drug metabolism and disposition Vol. 46; no. 8; pp. 1075 - 1082
• Main Authors: Shen, Hong, Christopher, Lisa, Lai, Yurong, Gong, Jiachang, Kandoussi, Hamza, Garonzik, Samira, Perera, Vidya, Garimella, Tushar, Humphreys, W Griffith
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics, Inc 01.08.2018
• Subjects: Adult; Anions; Biological Transport - drug effects; Biological Transport - physiology; Biomarkers; Biomarkers - metabolism; Coproporphyrins - genetics; Coproporphyrins - metabolism; Diltiazem; Drug interaction; Drug interactions; Drug Interactions - physiology; Genotype; Genotypes; Humans; Inhibition; Itraconazole; Liver-Specific Organic Anion Transporter 1 - antagonists & inhibitors; Liver-Specific Organic Anion Transporter 1 - genetics; Liver-Specific Organic Anion Transporter 1 - metabolism; Male; Middle Aged; Oral administration; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; Organic anion transporting polypeptide; Polypeptides; Populations; Predictions; Rifampin; Rifampin - pharmacology; Sensitivity analysis; Solute Carrier Organic Anion Transporter Family Member 1B3 - antagonists & inhibitors; Solute Carrier Organic Anion Transporter Family Member 1B3 - genetics; Solute Carrier Organic Anion Transporter Family Member 1B3 - metabolism; Substrates; Transportation; Young Adult
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.118.081125

In a recent study, limited to South Asian Indian subjects ( = 12), coproporphyrin (CP) I and CPIII demonstrated properties appropriate for an organic anion-transporting polypeptide (OATP) 1B endogenous probe. The current studies were conducted in healthy volunteers of mixed ethnicities, including black, white, and Hispanic subjects, to better understand the utility of these biomarkers in broader populations. After oral administration with 600 mg rifampin, values were 2.8-, 3.7-, and 3.6-fold higher than predose levels for CPI and 2.6-, 3.1-, and 2.4-fold higher for CPIII, for the three populations, respectively. These changes in response to rifampin were consistent with previous results. The sensitivity toward OATP1B inhibition was also investigated by evaluating changes of plasma CP levels in the presence of diltiazem and itraconazole [administered as part of an unrelated drug-drug interaction (DDI) investigation], two compounds that were predicted to have minimal inhibitory effect on OATP1B. Administration of diltiazem and itraconazole did not increase plasma CPI and CPIII concentrations relative to prestudy levels, in agreement with predictions from in vitro parameters. Additionally, the basal CP concentrations in subjects with c.521TT genotype were comparable to those with c.521TC genotype, similar to studies with probe substrates. However, subjects with c.388AG and c.388GG genotypes (i.e., increased OATP1B1 transport activity for certain substrates) had lower concentrations of CPI than those with c.388AA. Collectively, these findings provide further evidence supporting the translational value of CPI and CPIII as suitable endogenous clinical probes to gauge OATP1B activity and potential for OATP1B-mediated DDIs.