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Kinetics of hydralazine and its main metabolites in slow and fast acetylators
Author(s) -
Reece Phillip A,
Cozamanis Irene,
Zacest Rudolf
Publication year - 1980
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1980.234
Subject(s) - chemistry , metabolite , pharmacokinetics , volume of distribution , kinetics , oral administration , chromatography , distribution volume , steady state (chemistry) , hydralazine , pharmacology , medicine , biochemistry , physics , quantum mechanics , blood pressure
Kinetics of hydralazine (HP) and its metabolites, hydralazine pyruvic acid hydrazone (HPPAH) and 3‐methyl‐s‐triazolo[3,4‐a]phthalazine (MTP), was examined in five slow and five fast acetylators after single oral and intravenous doses of HP on separate occasions at least 1 wk apart. Blood samples were collected over a 10‐hr period and levels of the drug and metabolites determined by sensitive high‐performance liquid chromatographic ‐fluorescence assay. After intravenous administration HP plasma concentrations were fitted to a two‐compartment model and the following mean kinetic parameters were obtained for the slow and fast acetylators: terminal half Ufes (t 1/2 s), 0.677 and 0.664 hr; total plasma clearances, 7.77 and 8.86 l /hr/kg; distribution pseudoequilibrium t½s, 4.80 and 5.40 min; volumes of plasma compartment, 2.53 and 3.01 l /kg; steady‐state volumes of distribution, 5.71 and 6.37 l /kg; and apparent volume of distribution (calculated from total plasma clearance divided by β, where β is the compound rate constant expressing the rate of loss of drug from the body after pseudoequilibrium is achieved), 7.25 and 8.16 l /kg. None was different (i.e., statistically) for the two groups. Of those measured, the major plasma metabolite was HPPAH, which together with HP constituted most of the “apparent HP” measured by published nonspecific assays. The mean areas under the curve (AUCs) of MTP were 0.501 and 1.014 μm/l/hr (p < 0.01) in the slow and fast acetylators. After oral doses to the slow and fast acetylators, mean terminal HP t½s were 0.474 and 0.437 hr (p > 0.6) and bioavailability, 35.4% and 16.2% (p < 0.001). With this route of administration, HPPAH was the major plasma metabolite in the slow acetylators and MTP the major metabolite in the fast acetylators. The mean AUCs of MTP (corrected for dose differences) were 1.50 and 3.98 μm/l/hr (p < 0.001) in the slow and fast acetylators. Clinical Pharmacology and Therapeutics (1980) 28 , 769–778; doi: 10.1038/clpt.1980.234