Mechanism-based pharmacokinetic modeling to evaluate transporter-enzyme interplay in drug interactions and pharmacogenetics of glyburide

The purpose of this study is to characterize the involvement of hepato-biliary transport and cytochrome-P450 (CYP)-mediated metabolism in the disposition of glyburide and predict its pharmacokinetic variability due to drug interactions and genetic variations. Comprehensive in vitro studies suggested that glyburide is a highly permeable drug with substrate affinity to multiple efflux pumps and to organic anion transporting polypeptide (OATP)1B1 and OATP2B1. Active hepatic uptake was found to be significantly higher than the passive uptake clearance (15.8 versus 5.3 μL/min/10(6)-hepatocytes), using the sandwich-cultured hepatocyte model. In vitro, glyburide is metabolized (intrinsic clearance, 52.9 μL/min/mg-microsomal protein) by CYP3A4, CYP2C9, and CYP2C8 with fraction metabolism of 0.53, 0.36, and 0.11, respectively. Using these in vitro data, physiologically based pharmacokinetic models, assuming rapid-equilibrium between blood and liver compartments or permeability-limited hepatic disposition, were built to describe pharmacokinetics and evaluate drug interactions. Permeability-limited model successfully predicted glyburide interactions with rifampicin and other perpetrator drugs. Conversely, model assuming rapid-equilibrium mispredicted glyburide interactions, overall, suggesting hepatic uptake as the primary rate-determining process in the systemic clearance of glyburide. Further modeling and simulations indicated that the impairment of CYP2C9 function has a minimal effect on the systemic exposure, implying discrepancy in the contribution of CYP2C9 to glyburide clearance.

Medienart:

E-Artikel

Erscheinungsjahr:

2014

Erschienen:

2014

Enthalten in:

Zur Gesamtaufnahme - volume:16

Enthalten in:

The AAPS journal - 16(2014), 4 vom: 10. Juli, Seite 736-48

Sprache:

Englisch

Beteiligte Personen:

Varma, Manthena V S [VerfasserIn]
Scialis, Renato J [VerfasserIn]
Lin, Jian [VerfasserIn]
Bi, Yi-An [VerfasserIn]
Rotter, Charles J [VerfasserIn]
Goosen, Theunis C [VerfasserIn]
Yang, Xin [VerfasserIn]

Links:

Volltext

Themen:

9035-51-2
Cytochrome P-450 Enzyme System
Enzyme Inhibitors
Glyburide
Hypoglycemic Agents
Isoenzymes
Journal Article
Organic Anion Transporters
SX6K58TVWC

Anmerkungen:

Date Completed 06.02.2015

Date Revised 21.10.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1208/s12248-014-9614-7

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM238352676