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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
pharmacology, toxicology and pharmaceutics
In vitro and in silico identification and characterization of thiabendazole as a mechanism-based inhibitor of CYP1A2 and simulation of possible pharmacokinetic drug-drug interactions
Drug Metabolism and Disposition, Volume 37, No. 6, Year 2009
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Description
Thiabendazole (TBZ) and its major metabolite 5-hydroxythiabendazole (5OH-TBZ) were screened for potential time-dependent inhibition (TDI) against CYP1A2. Screen assays were carried out in the absence and presence of NADPH. TDI was observed with both compounds, with kinact and KI values of 0.08 and 0.02 min-1 and 1.4 and 63.3 μM for TBZ and 5OH-TBZ, respectively. Enzyme inactivation was time-, concentration-, and NADPH-dependent. Inactivation by TBZ was irreversible by dialysis and oxidation by potassium ferricyanide, and there was no protection by glutathione. 5OH-TBZ was a weak TDI of CYP1A2, and enzyme activity was recovered by dialysis. IC 50 determination of TBZ and 5OH-TBZ showed both compounds to be potent inhibitors, with IC50 values of 0.83 and 13.05 μM, respectively. IC50 shift studies also demonstrated that TBZ was a TDI of CYP1A2. In silico methods identified the thiazole group as a TDI fragment and predicted it as the site of metabolism. The observation pointed to epoxidation of the thiazole and the benzyl rings of TBZ as possible routes of metabolism and mechanisms of TDI. Drug-drug interaction (DDI) simulation studies using SimCyp showed good predictions for competitive inhibition. However, predictions for mechanism-based inhibition (MBI)-based DDI were not in agreement with clinical observations. There was no TBZ accumulation upon chronic administration of the drug. The in vitro MBI findings might therefore not be capturing the in vivo situation in which the proposed bioactivation route is minor. This might be the case for TBZ in which, in vivo, UDP glucuronosyltransferases and sulfanotransferase metabolize and eliminate the 5OH-TBZ. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.
Authors & Co-Authors
Thelingwani, Roslyn Stella
Zimbabwe, Harare
African Institute of Biomedical Science and Technology
South Africa, Cape Town
University of Cape Town
Zvada, Simbarashe Peter
Zimbabwe, Harare
African Institute of Biomedical Science and Technology
Dolgos, Hugues
Sweden, Sodertalje
Astrazeneca Sweden
Ungell, Anna Lena B.
Sweden, Sodertalje
Astrazeneca Sweden
Masimirembwa, Collen Mutowembwa
Zimbabwe, Harare
African Institute of Biomedical Science and Technology
Statistics
Citations: 31
Authors: 5
Affiliations: 3
Identifiers
Doi:
10.1124/dmd.108.024604
ISSN:
00909556
e-ISSN:
1521009X
Research Areas
Noncommunicable Diseases