Transporter–enzyme interplay and the hepatic drug clearance: what have we learned so far?

ABSTRACT

Introduction: Transporters and enzymes play an important role in absorption, distribution, clearance and elimination of drugs.

Areas covered: This review provides an overview of the extended clearance concept and usefulness of extended clearance classification system (ECCS) in early identification of predominant clearance mechanisms. Clinical studies demonstrating transporter–enzyme interplay, challenges in scaling clearance from in vitro systems, utility of animal models and modeling approaches for evaluating hepatic clearance and drug–drug interactions are reviewed.

Expert opinion: Clinical evidence exists supporting organic anion transporting peptide (OATP)1B and drug metabolizing enzymes involvement in clearance of ECCS class 1B drugs. Emerging evidence point toward contribution of organic cation transporter (OCT)1 to hepatic uptake of cationic drugs. Although, limited clinical evidence is presented, preclinical studies and modeling suggests organic anion transporter (OAT)2–enzyme interplay in clearance of class 1A drugs. Data from in vitro assays and preclinical models coupled with physiologically based modeling approaches are key for understanding transporter–enzyme interplay, enabling prediction of pharmacokinetics, tissue exposure and drug interactions. Current methodologies incur limitations and emphasis should be placed on the development of physiologically relevant in vitro models and characterize in vivo animal models to inform mechanistic modeling and improve confidence in prospective predictions.

KEYWORDS:

• Drug–drug interactions
• drug transporters
• extended clearance concept
• extended clearance classification system
• metabolism
• physiologically based pharmacokinetic modeling

Article highlights

• Membrane transporters (uptake and efflux) and drug metabolizing enzymes are expressed in the major drug eliminating organs. Several clinical studies indicate that transporter–enzyme interplay determine the overall hepatic drug clearance and magnitude of drug–drug interactions of many drugs.

• Extended clearance concept allows for integration of uptake, efflux and metabolism clearances to assess the rate-determining step and the overall clearance. Extended clearance classification system (ECCS) helps in early identification of predominant clearance mechanism and potential for transporter–enzyme interplay.

• Mechanistic assessment integrating transport and metabolic data via physiologically based pharmacokinetic modelling is important for predicting clearance and drug–drug interactions. Intrinsic clearance data generated using current in vitro systems expressing human transporters and enzymes generally underpredict in vivo clearance. However, recent suggested adding serum albumin to the incubation media in hepatic uptake assays improves clearance predictions with relatively small empirical scaling factors. Additional modifications to the assay protocols while considering physiologically relevant conditions, such as in microphysiological systems, may help in achieving expression and functional activity in the in vitro systems comparable to in vivo.

• Animal models such as knock-out and transgenic rodents may help in characterizing clearance mechanisms and transporters involved in hepatic clearance of drugs. Data generated in non-human primate models showed promise in assessing clearance and drug–drug interaction risk when hepatic transporters are involved.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.