Abstract
In a recent study, limited to South Asian Indian subjects (n=12), coproporphyrin I and III (CPI and CPIII) demonstrated properties appropriate for an OATP1B endogenous probe (Lai et al., 2016). 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, AUC(0-24h) 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 3 populations, respectively. These changes in response to rifampin were consistent with previous results. The sensitivity towards OATP1B inhibition was also investigated by evaluating changes of plasma CP levels in the presence of diltiazem and itraconazole (administered as an part of unrelated 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 SLCO1B1 c.521TT genotype were comparable to those with SLCO1B1 c.521TC genotype, similar to studies with probe substrates. However, subjects with SLCO1B1 c.388AG and c.388GG genotypes, (i.e. increased OATP1B1 transport activity for certain substrates), had lower concentrations of CPI than those with SLCO1B1 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.
- The American Society for Pharmacology and Experimental Therapeutics