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Journal of Pharmacology and Toxicology

Year: 2006  |  Volume: 1  |  Issue: 5  |  Page No.: 447 - 455

Molecular Modelling Analysis of the Metabolism of Isoniazid

Fazlul Huq


Isoniazid is the cornerstone of therapy against tuberculosis which is a global health problem of increasing dimension. Isoniazid is metabolized in the liver by acetylation and hydroxylation. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that isoniazid and its metabolites differ to some extent in their solvation energy, surface charge distribution, dipole moment, thermodynamic stability and kinetic lability. The metabolites hydrazine and acetylhydrazine are believed to be responsible for isoniazid induced liver toxicity. However, the results of molecular modelling analyses show that both the metabolites are kinetically inert. It is possible that these are spontaneously converted to more reactive metabolites pyruvate hydrazone and 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid. The charged nature of the surface of isoniazid and its metabolites indicates that the compounds may interact with biomolecules electrically. It also explains why the molecules are soluble in water.

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