Pharmacokinetics and Biotransformation of Hydralazine Acetone Hydrazone, a Metabolite of Hydralazine, in the Rat

Iwaki, Masaya; Ogiso, Taro; Ito, Yoshimasa

doi:10.1002/jps.2600781018

Cited by 6 publications

(3 citation statements)

References 18 publications

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“…195 The interconversions of hydralazine and HAH have been demonstrated in rats and rabbits. 196,197 Quinones The interconversion of vitamin K1 and vitamin-Kl-2,3-epoxide was found in dogs198 and human^. '^^>^^ The epoxide has the same activity as vitamin K1 in stimulating prothrombin synthesis in vitamin-deficient animals.201 Vitamin K1 is first converted to vitamin-K1 hydroquinone by NAD(P)H in the presence of vitamin-K reductase and then to vitamin-Kl epoxide.…”

Section: Carboxylic Acidsmentioning

confidence: 99%

Pharmacokinetics of reversible metabolic systems

Cheng

Jusko

1993

Biopharm & Drug Disp

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Section: Carboxylic Acidsmentioning

confidence: 99%

Pharmacokinetics of reversible metabolic systems

Cheng

Jusko

1993

Biopharm & Drug Disp

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“…Its metabolite HAH degrades accompanied by simultaneous hydrolysis to Hz with first-order rate (t 1/2 = 2.3 h) and acetone [42]. In the presence of pyruvate formation of HPH takes place in rats either after conversion to parent drug Hz or directly with HAH to a far higher extent [43]. Further in vitro and in vivo experiments confirm that the stable hydrazones, HPH and hydralazine α-ketoglutaric acid hydrazone did not hydrolyze to Hz in vitro, buffer, or plasma.…”

mentioning

confidence: 99%

Isoniazid is Not a Lead Compound for its Pyridyl Ring Derivatives,Isonicotinoyl Amides, Hydrazides, and Hydrazones: A Critical Review

Scior¹,

Garcés-Eisele

2006

CMC

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The relationships between structure, disintegration and antituberculotic in vitro activity were studied for over 200 derivatives of isonicotinic acid hydrazide (isoniazid, INH). Conclusive evidence reflects that many compounds do not withstand the in vitro conditions. A pH dependant partial hydrolysis to INH occurs in the case of hydrazones, in analogy to well-known benzoic acid esters. Hydrazides and amides are cleaved into isonicotinic acid. In general, antimycobacterial potencies drop against INH except for two outliers probably with additional unspecific toxicity of their residues. Analyzing the complexity and heterogeneity of molecular events, trends linked to hydrolysis are found when structural features are clustered. Hammett sigma constants correlate to pK(a) values possessing a twofold descriptive meaning: (i) the cardinal increase of partial positive charge of the reaction center towards nucleophilic water attack and (ii) the ionization crucial for mycobacterial cell permeation through porins or lipid barriers. We review the literature concluding that many so-called "novel leads" are nothing else than precursors of an INH-based scaffold. In addition, INH ring-substitution or analogous backbones never achieve the efficiency of INH, itself a prodrug, which accumulates in Mycobacterium tuberculosis in form of its intrabacterial active principle(s) to which it is an optimal transport vehicle, evidencing that INH is not a promising lead compound at all.

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“…These in vitro active concentrations are significantly higher than the maximum concentrations reached in vivo after acute administration of a single therapeutic dose of hydralazine to rats [19,20]. In addition, the in vivo plasma half-life of hydralazine in rats is relatively short, whereas its pharmacological activity is prolonged.…”

Section: Introductionmentioning

confidence: 99%