Absorption and Disposition of Coproporphyrin I (CPI) in Cynomolgus Monkeys and Mice: Pharmacokinetic Evidence to Support the Use of CPI to Inform the Potential for Organic Anion-Transporting Polypeptide Inhibition

Abstract

Despite a recent expansion in the recognition of the potential utility of coproporphyrin (CP) as an endogenous biomarker of organic anion-transporting polypeptide (OATP) 1B activity, there have been few detailed studies of CP's pharmacokinetic behavior and an overall poor understanding of its pharmacokinetic fate from tissues and excretion. Here, we describe the pharmacokinetics of octadeuterium-labeled coproporphyrin I (CPI-d8) in cynomolgus monkeys following oral and intravenous administration. CPI-d8 has a half-life and bioavailability of 7.6 hours and 3.2%, respectively. Cynomolgus monkeys received oral cyclosporin A (CsA) at 4, 20, and 100 mg/kg which yielded maximum blood concentrations (C max ) and area under the plasma concentration-time curve (AUC) values of 0.

Absence of OATP1B (Organic Anion–Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression

“…Our recent study indicated that CPI was subjected to limited oral absorption with bioavailability of less than 5% in monkeys and cyclosporin A did not significantly affect the CPI bioavailability (Gu et al, 2020), suggesting that the altered intestinal MRP2 is unlikely to affect the plasma concentration of endogenous CPI. The increased MRP2 expression in the liver after repeated RIF dosing ( Figure 4A) may contribute to enhanced CP clearance from the blood.…”

“…The final version may differ from this version. and OATP1B, respectively (Diczfalusy et al, 2011, Kasichayanula et al, 2014, Li et al, 2014, Tahara et al, 2019, Takehara et al, 2019, Gu et al, 2020. Therefore, 4βHC, CPI, and CPIII were selected as in vivo probes of CYP3A and OATP1B activities, and we studied the day-to-day change from predose plasma levels and throughout the entire study with the strong PXR activator RIF.…”

PBPK Model of Coproporphyrin I: Evaluation of the Impact of SLCO1B1 Genotype, Ethnicity, and Sex on its Inter‐Individual Variability

“…where C blood , C LV , C LT , A bile , and A urine are the concentration (C) or amount (A) of CPI in the blood (central), liver vascular, liver tissue, bile, and urine compartments, respectively. The parameters 29 and low bioavailability of labeled CPI in monkeys, 30 this process was assumed to be insignificant for the PK of CPI and was not considered in the current model development.…”

“…Enterohepatic circulation of CPI was not considered in our model, supported by the recent studies. 29,30 For pragmatic reasons, concentration of rifampicin in the central compartment was used as inhibitory concentration affecting CPI CL active,u ; any potential rifampicin concentration gradient between blood and hepatic inlet was not considered. This assumption may potentially underestimate rifampicin OATP1B Ki, but the covariates estimated as relative changes are not likely to be sensitive to this assumption.…”

“…It is a metabolically stable substrate of OATP1B1 and 1B3, as well as MRP2 and MRP3 transporters 18–23 . CPI‐drug interactions reported so far in human 22,24–28 and preclinical species 19,29,30 suggest that this biomarker is expected to closely follow the perpetrator concentration–time profile. In contrast to other OATP1B biomarkers, circadian rhythm or food intake are not likely to cause interindividual variability in its plasma baseline 19,24 …”