Faculty Collaboration Database

Carbamazepine: a 'blind' assessment of CVP-associated metabolism and interactions in human liver-derived in vitro systems. Xenobiotica 2001 Jun;31(6):321-43

Date

08/22/2001

Pubmed ID

11513246

DOI

10.1080/00498250110055479

Scopus ID

2-s2.0-17844407393 (requires institutional sign-in at Scopus site)   61 Citations

Abstract

1. The ability of various in vitro systems for CYP enzymes (computer modelling, human liver microsomes, precision-cut liver slices, hepatocytes in culture, recombinant enzymes) to predict various aspects of in vivo metabolism and kinetics of carbamazepine (CBZ) was investigated. 2. The study was part of the EUROCYP project that aimed to evaluate relevant human in vitro systems to study drug metabolism. 3. CBZ was given to the participating laboratories without disclosing its chemical nature. 4. The most important enzyme (CYP3A4) and metabolic route (10,11-epoxidation) were predicted by all the systems studied. 5. Minor enzymes and routes were predicted to a different extent by various systems. 6. Prediction of a clearance class, i.e. slow clearance, was correctly predicted by microsomes, slices, hepatocytes and recombinant enzymes (CYP3A4). 7. The 10,11-epoxidation of CBZ by the recombinant CYP3A4 was enhanced by the addition of exogenous cytochrome-b5, leading to a considerable over-prediction. 8. Induction potency of CBZ was predicted in cultured hepatocytes in which 7-ethoxycoumarin O-deethylase was used as an index activity. 9. It seems that for a principally CYP-metabolized substance such as CBZ, all liver-derived systems provide useful information for prediction of metabolic routes, rates and interactions.

Author List

Pelkonen O, Myllynen P, Taavitsainen P, Boobis AR, Watts P, Lake BG, Price RJ, Renwick AB, Gómez-Lechón MJ, Castell JV, Ingelman-Sundberg M, Hidestrand M, Guillouzo A, Corcos L, Goldfarb PS, Lewis DF

MESH terms used to index this publication - Major topics in bold

Anticonvulsants
Carbamazepine
Cells, Cultured
Computer Simulation
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System
Epoxy Compounds
Hepatocytes
Humans
In Vitro Techniques
Kinetics
Liver
Microsomes, Liver
Mixed Function Oxygenases
Recombinant Proteins