Transporter-Mediated Disposition, Clinical Pharmacokinetics and Cholestatic Potential of Glyburide and Its Primary Active Metabolites.

Abstract

Glyburide is widely used for the treatment of type 2 diabetes. We studied the mechanisms involved in the disposition of glyburide and its pharmacologically active hydroxy metabolites M1 and M2b and evaluated their clinical pharmacokinetics and the potential role in glyburide-induced cholestasis employing physiologically based pharmacokinetic (PBPK) modeling. Transport studies of parent and metabolites in human hepatocytes and transfected cell systems imply hepatic uptake mediated by organic anion-transporting polypeptides. Metabolites are also subjected to basolateral and biliary efflux by P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated proteins, and are substrates to renal organic anion transporter 3. A PBPK model in combination with a Bayesian approach was developed considering the identified disposition mechanisms. The model reasonably described plasma concentration time profiles and urinary recoveries of glyburide and the metabolites, implying the role of multiple transport processes in their pharmacokinetics. Predicted free liver concentrations of the parent (∼30-fold) and metabolites (∼4-fold) were higher than their free plasma concentrations. Finally, all three compounds showed bile salt export pump inhibition in vitro; however, significant in vivo inhibition was not apparent for any compound on the basis of a predicted unbound liver exposure-response effect model using measured in vitro IC50 values. In conclusion, this study demonstrates the important role of multiple drug transporters in the disposition of glyburide and its active metabolites, suggesting that variability in the function of these processes may lead to pharmacokinetic variability in the parent and the metabolites, potentially translating to pharmacodynamic variability.

• Authors: Rui Li, Yi-An Bi, Anna Vildhede, Renato J Scialis, Sumathy Mathialagan, Xin Yang, Lisa D Marroquin, Jian Lin, Manthena V S Varma
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 45 Issue 7 Pg. 737-747 (07 2017) ISSN: 1521-009X [Electronic] United States
• PMID: 28438781 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• ATP-Binding Cassette Transporters
• Membrane Transport Proteins
• Multidrug Resistance-Associated Proteins
• Organic Anion Transporters
• Glyburide

Topics

• ATP-Binding Cassette Transporters (metabolism)
• Bayes Theorem
• Biological Transport (physiology)
• Cell Line
• Cholestasis (metabolism)
• Glyburide (metabolism, pharmacokinetics)
• HEK293 Cells
• Hepatocytes (metabolism)
• Humans
• Liver (metabolism)
• Membrane Transport Proteins (metabolism)
• Multidrug Resistance-Associated Proteins (metabolism)
• Organic Anion Transporters (metabolism)