Identification of the decomposition products of hydralazine hydrazones with three endogenous ketones and kinetic study of the formation of 3-methyl-s-triazolo(3,4-a)phthalazine from hydralazine and pyruvic acid.

Nakano, Masahiro; Tomitsuka, Toshiaki; Juni, Kazuhiko

doi:10.1248/cpb.28.3407

Cited by 3 publications

(1 citation statement)

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“…However, quantitative measurements of these hydrazones in urine or plasma have not been reported. Recently, Nakano et al (1980) demonstrated that both of these hydrazones can degrade to phthalzinone. Many other hydrazones have been postulated, including the acetaldehyde adduct which can oxidatively cyclise to yield s-methyltriazolo [3,4a] phthalazine (O'Donnell et aI., I 979a,b).…”

Section: Eliminationmentioning

confidence: 99%

Clinical Pharmacokinetics of Hydralazine

Ludden

McNay

Shepherd

et al. 1982

Clinical Pharmacokinetics

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Hydralazine is one of the most (requent(v prescribed drugs for the treatment of moderate to severe hypertellsion. In addition, it is being used il/creasingly for the treatment of congestive heart failure when more traditional approaches fail. Although hydralazine has been in clinical use fiJr 30 years, there is inSl({ficient information concerning dose-blood concentration and blood collcentration-response relationships to formulate rational approaches for dosage indit'idualisatirm. This paucity of data is primari(l' due to the fact that many previous methods Ii)r measuremelll of hydralazine in plasma were non-selective and measured circulating, inactil'e metabolites. Recently, more selectil'e procedures hal'e been developed and are being applied to the study ()f the pharmacokinetic behaviour ()f hydralazine in man.Hydralazine is l'ery unstable in plasma in vitro (half~life of approximately 6 minutes at 37°e) and deril'atisation of samples must be carried out very rapidly to at'oid loss of drug. Studies in healthy mlullleers and hypertensil'e patients indicated that after oral administration hydralazine undergoes extensil'e acetylator phenotype-dependent first-pass metabolism. Results usillg selectil'e assay procedures indicate a mean fractional al'ailability of about 0.30 to 0.35Ii)r slow acetylators and 0.10 to 0.16 /iir rapid acetylators. Food may enhance the bioal'ailability. There is el'idence that the first-pass effect is saturable. After in!ral'enous administration acetylator phenotype is 110t a maior determinalll (If hydralazille dispositioll. This indicates that a largelraction of systemic clearance is via metabolic pathways independelll of acetylator phenotype. Thefact that hydralazine rapidly fimns a hydrazone with pYf'lIl'ic acid ill plasma or whole blood can account for a signi(icallf proportion ofs,l'stemic clearance. HOl1'el'er, formation of other hydrazones or adducts cannot be ruled out. Besides acetylatirm, oxidatil'e metabolism accou!1ls for a siglli(icalll proportion of elimination since 4 -(2 -acetylhydrazino) phthalazin-I-one is a maior urinary metabolite. This compound Call only occur if oxidation precedes acetylation since the product ()( hydralazine acetylation is 3-methyl-s-triazolo [3,4a} phtlralazine and would not yield the 2-acetylhydrazino deril'atil'e upon subsequent oxidatirm. Less thall 10 % of a dose is prese!1l in urine as hydralazine or acidlabile coniugates o( hydralazine. Clearance and apparelll mlume o( distribution appear to be lower and hal(-hIe longer in older hypertensil'e patients thall in young healthy l'olullleers, but the 2 populations were sllIdied by di!krellt research groups using dif(erelll experimelllal designs and dUkrelll assay methods. Further studies are needed to determine whether the dif(erences really exist. Similar(l', the e(lects o( renalfailure on the pharmacokinetics of hydralazine are not yet understood. In addition, the use o(hydralazine ill resistalll congestil'e heart failure requires that the influences o( this disease state on kinetics be determi...

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Section: Eliminationmentioning

confidence: 99%