Clinical Investigation of Coproporphyrins as Sensitive Biomarkers to Predict Mild to Strong OATP1B-Mediated Drug–Drug Interactions

Abstract

Our results demonstrate the selectivity of CPI and CPIII towards the OATP1B/MRP pathway, and the herein reported data further underline the potential of CPI and CPIII as selective and sensitive clinical biomarkers to quantify OATP1B-mediated DDIs.

Expanded Physiologically‐Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction

“…( Figure c ). When compared with the other two reports, the observed profiles by Kunze et al . displayed an apparent delay for blood CP‐I levels to increase following single or repeated oral dosing of 600 mg rifampicin, and this delay was not well captured by our PBPK model and the obtained parameters from the analysis of Takehara et al .…”

“…Three recent reports provided the clinical data on the blood CP‐I concentration‐time profiles impacted by single or repeated oral dosing of rifampicin . Our PBPK model incorporated the components for induction of OATP1B and inhibition of OATP1B/MRP2 by rifampicin ( Figure a ).…”

“…Our PBPK model and the obtained parameters from the analysis of Takehara et al . were used to predict blood profiles of CP‐I from the other two reports . The predicted profiles of CP‐I after a single oral dose of 600 mg rifampicin displayed a slight underestimation of the observed profiles by Lai et al .…”

PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3

“…(III) Finally, using the calculated in vivo K i,OATP1Bs for the probe substrate drugs, PBPK modeling and simulation would support the prediction of changes in substrate concentration‐time profiles, AUC, and C max caused by the NCE. Although some problems ascribed to experimental techniques in vitro remain to be solved (i.e., difficulty in obtaining reliable in vitro K i,u of highly lipophilic compounds due to nonspecific binding), translation of the effect of an NCE on CP‐I pharmacokinetics to effects on clinically used drugs is gradually becoming more accepted …”

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

“…In addition, only CPIII but not CPI was transported by OATP2B1 (Bednarczyk andBoiselle, 2015, Shen et al, 2017). While CPI was recently identified as a substrate for MRP3 and MRP2, localized on the sinusoidal and canalicular membranes of hepatocytes, respectively (Gilibili et al, 2017, Kunze et al, 2018, the OATP1B-mediated uptake is considered to be the rate-limiting step of the hepatic clearance of these endogenous substrates; the magnitude of MRPmediated DDI is generally small (less than 2-fold). Based on these findings and the higher plasma levels, CPI may be a more reliable endogenous biomarker for OATP1B transporters than CPIII.…”