The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates

TL;DR

This review explains how transport proteins move drug metabolites in the body, affecting drug safety and effectiveness.

Contribution

The paper compiles current knowledge on transporters involved in glucuronide and sulfate conjugate disposition.

Findings

Uptake transporters like OATs and OATPs help move drug conjugates into the liver and kidneys.

Efflux transporters like MRPs and BCRP expel conjugates into bile, urine, and the intestinal lumen.

Transporter activity influences drug toxicity, interactions, and differences between species.

Abstract

Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.

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