Glucuronidation of orally administered drugs and the value of nanocarriers in strategies for its overcome

Abstract

The gastrointestinal tract (GIT) plays a pivotal role in the absorption of orally administered drugs, with the small intestine serving as the primary site due to its extensive surface area and specialized cell types, including enterocytes and M cells. After oral administration, drugs are generally transported via the portal vein to the liver, where they undergo first-pass metabolism. This process involves various enzymatic reactions, including glucuronidation, facilitated by uridine diphosphate-glucuronosyltransferase (UGT), a major phase 2 reaction in mammalian metabolism.

UGTs conjugate glucuronic acid to a wide array of endogenous and exogenous substrates, enhancing their solubility and excretion, but significantly affecting the bioavailability and therapeutic efficacy of drugs. UGT enzymes are ubiquitously distributed across tissues, prominently in the liver, but also in the GIT, kidneys, brain, and other organs where they play crucial roles in xenobiotic metabolism.

Species-specific differences in UGT expression and activity impact the selection of animal models for pharmacological studies. Various experimental models – ranging from computational simulations (in silico) to laboratory experiments (in vitro) and animal studies (in vivo) – are employed throughout drug discovery and development to evaluate drug metabolism, including UGT activity.

Effective strategies to counter pre-systemic metabolism are critical for improving drug bioavailability. This review explores several approaches including prodrugs, co-administration of specific molecules or use of inhibiting excipients in formulations. Strategies incorporating these excipients in nanoformulations demonstrate notable increases in drug absorption and bioavailability.

This review highlights the importance of targeted delivery systems and excipient selection in overcoming metabolic barriers, aiming to optimize drug efficacy and patient outcomes.