Pharmacokinetics of hydralazine and its acid-labile hydrazone metabolites in relation to acetylator phenotype.
The pharmacokinetics of hydralazine (H) and its acid-labile hydrazone metabolites were compared in rapid and slow acetylators. Following a 20-mg intravenous infusion, the elimination half-life (t 1/2 beta) and the apparent volume of distribution of H did not differ between the two groups. Plasma clearance estimates approached hepatic blood flow. When a single 100-mg dose of H was given orally, the area under the plasma concentration-time curve (AUC) and a systemic availability (theta) in slow acetylators were, on the average, twice as high as in the rapid acetylators, indicating a difference in the extent of first-pass metabolism of the drug. Furthermore, the observed theta in the slow individuals exceeded theoretical predictions. Hence saturation of first-pass metabolism of H is suggested, and a nonlinear relationship between AUC and oral dose of H was indeed observed in the three subjects studied with two doses. The half-life of decline of the acid-labile metabolites was similar to the t 1/2 beta of H. The AUCs for metabolies were 4--12 times larger than for the parent drug. However, the ratio between the metabolite AUC and drug AUC did not differ irrespective of routes of administration or the acetylator status.
D000107:Acetylation; D000284:Administration, Oral; D000328:Adult; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D006801:Humans; D006830:Hydralazine / Q000097:blood / Q000378:metabolism*; D006835:Hydrazones / Q000378:metabolism*; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D010641:Phenotype; D013997:Time Factors
D006835:Hydrazones; D006830:Hydralazine