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J Pharm Sci. 2017 Sep;106(9):2357-2367. doi: 10.1016/j.xphs.2017.04.007. Epub 2017 Apr 14.

Identification of Endogenous Biomarkers to Predict the Propensity of Drug Candidates to Cause Hepatic or Renal Transporter-Mediated Drug-Drug Interactions.

Author information

1
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey 07033. Electronic address: Xiaoyan_Chu@merck.com.
2
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey 07033.

Abstract

Drug transporters expressed in liver and kidney play a critical role in the elimination of a wide range of drugs and xenobiotics and inhibition of these transporters may therefore cause clinically significant drug-drug interactions (DDIs). Currently, in vitro transporter inhibition data are used to assess the risk that a drug candidate may act as an inhibitor of a transporter in patients at clinically relevant exposures. However, this approach is hampered by low confidence in in vitro to in vivo extrapolations, and large inter-system and inter-laboratory variability in in vitro data. Several endogenous compounds have been identified as substrates of drug transporters. Determining the impact of perpetrator drugs on the plasma or urinary exposure of these potential endogenous biomarkers in humans is being explored as an alternative approach to assess the DDI liability of drug candidates, especially in early drug development. In this review, we provide an overview of recently identified biomarkers used to study the inhibition of hepatic and renal transporters; summarize the methods and strategies employed to identify biomarkers; and discuss the utility, limitation, and future direction of biomarker approaches to predict transporter-mediated DDIs.

KEYWORDS:

drug-drug interactions; endogenous biomarkers; transporters

PMID:
28416420
DOI:
10.1016/j.xphs.2017.04.007
[Indexed for MEDLINE]

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