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Pharmacokinetics of isoniazid metabolism in man

Abstract

Detailed pharmacokinetic studies undertaken on a slow and a rapid acetylator of isoniazid enabled approximate first-order rate constants to be calculated for the metabolic processes involved in the conversion of isoniazid to acetylisoniazid, isonicotinic acid, isonicotinylglycine, monoacetylhydrazine, and diacetylhydrazine, and their excretion in the urine. Further studies of the metabolism of isoniazid were carried out on another 17 slow and 11 rapid acetylators. The major pathway of isoniazid metabolism was acetylation. The rapid acetylators acetylated isoniazid 5–6 times more rapidly than the slow acetylators. Acid-labile hydrazones were also formed, and some isoniazid was hydrolyzed directly to isonicotinic acid. The major metabolic route for the formation of isonicotinic acid from isoniazid was via acetylisoniazid. Cleavage of acetylisoniazid in the body resulted in the formation of monoacetylhydrazine, which was then acetylated polymorphically to diacetylhydrazine in a manner analogous to the acetylation of isoniazid. Individuals differed in their ability to conjugate isonicotinic acid with glycine, and these differences were unrelated to the rates at which isoniazid was acetylated. The conjugation of isonicotinic acid with glycine and the acetylation of isoniazid appeared to be partially saturated in vivoafter the administration of doses of as little as 250 mg of either compound.

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Ellard, G.A., Gammon, P.T. Pharmacokinetics of isoniazid metabolism in man. Journal of Pharmacokinetics and Biopharmaceutics 4, 83–113 (1976). https://doi.org/10.1007/BF01086149

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  • DOI: https://doi.org/10.1007/BF01086149

Key words

  • isoniazid
  • acetylisoniazid
  • acetylhydrazine
  • isonicotinic acid
  • acetylation
  • polymorphism
  • glycine conjugation
  • saturable metabolic processes