Proteomics-informed Modeling Reveals Glucuronidation as a Transport Mechanism for Drugs and Endobiotics
Date: March 21 2023
Presenter(s): Bhagwat Prasad, PhD
Presenter: Bhagwat Prasad, Phd, Associate professor, Washington State University
Summary:
Glucuronidation is often considered as a mechanism that facilitates water solubility and excretion of drugs from the body. However, the enzymes involved in glucuronidation, i.e., uridine 5'-diphospho-glucuronosyltransferases (UGTs) are membrane bound proteins that are localized in the endoplasmic reticulum (ER) facing the lumen. This suggests that glucuronide metabolites are produced in the ER lumen, and they require efflux mechanisms to get sequentially transported from the ER lumen to cytosol and then to the blood before excretion from the body. Moreover, the biliary or apical efflux of glucuronide metabolites from the liver and intestine into intestinal lumen is an important mechanism of enterohepatic recycling through deconjugation by gut bacterial glucuronidases (GUS). There are numerous examples of glucuronide metabolites that show greater half-lives than the parent compounds indicating that these metabolites are recycled in the body. We have demonstrated using proteomics-informed modeling that glucuronide metabolites work in tandem with the efflux as well as uptake transporters. Thus, glucuronidation doesn’t always work as an elimination mechanism, but this process facilitates the transport of the parent compounds. Case studies of testosterone, irinotecan, and cannabinoids will be shared to demonstrate that such “UGT-transporter-GUS axis” is important in predicting the fate of UGT mediated drug metabolism. Further, this integrated mechanism hints towards the role of remote signaling in regulation of tissue specific expression of UGTs, e.g., higher expression of UGT2B17 in the intestine.
About the presenter:
PRASAD, Bhagwat, PhD
Assistant Professor Department of Pharmaceutics, Washington State University, Seattle, WA, US
Biography
Before joining as an assistant professor at University of Washington, Dr. Prasad worked as a postdoc fellow and a lead scientist of UW Research Affiliate Program on Transporters (UWRAPT). Dr. Prasad obtained M.S. (Pharm) in 2006 and Ph.D. in 2010 in Pharmaceutical Sciences from NIPER, Mohali, India. Dr. Prasad has published 55 peer-reviewed international papers and >70 conference abstracts and delivered >30 invited talks. Dr. Prasad also worked in Drug discovery division of Ranbaxy Research laboratories in India.
