Pharmacokinetics of hydralazine and its acid-labile hydrazone metabolites in relation to acetylator phenotype

Abstract

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.

Effect of N‐Acetyltransferase 2 Genotype on the Pharmacokinetics of Hydralazine During Pregnancy

“…In this study we characterized for the first time the PK of oral hydralazine and its metabolite MTP during pregnancy. Similar to previous reports in the nonpregnant population, oral hydralazine PK during pregnancy exhibited dependence on NAT2 genotype . Pregnant subjects with NAT2 RA genotypes exhibited significantly higher apparent oral clearance and apparent oral volume of distribution of hydralazine compared with women with SA genotypes.…”

“…Similar to previous reports in the nonpregnant population, oral hydralazine PK during pregnancy exhibited dependence on NAT2 genotype. 13,30,44,45 Pregnant subjects with NAT2 RA genotypes exhibited significantly higher apparent oral clearance and apparent oral volume of distribution of hydralazine compared with women with SA genotypes. In addition, the MTP-to-hydralazine AUC ratio was Figure 5.…”

“…This difference in first‐pass metabolism can be explained by genetically determined differential expression of NAT2 in the intestines and liver . In nonpregnant adults, the peak plasma concentration of hydralazine occurs within an hour after dose, and the elimination half‐life typically ranges from 1 to 4 hours …”

“…[27][28][29] In nonpregnant adults, the peak plasma concentration of hydralazine occurs within an hour after dose, and the elimination half-life typically ranges from 1 to 4 hours. 13,30,31 Earlier studies of hydralazine exposure during gestation were limited to blood samples collected at the time of delivery or postpartum. 32,33 These studies demonstrated transplacental fetal exposure to hydralazine, with a mean umbilical cord-to-maternal plasma concentration ratio of 2 ± 2.5 at the time of birth.…”

Nanomedicine strategies for treatment of secondary spinal cord injury

“…Some patients who metabolize the compound rapidly have been shown to exhibit lupuslike symptoms. 79 Therefore, a therapy that could concentrate hydralazine locally without lowering blood pressure or invading other tissues would have great potential for SCI patients. Hydralazine treatment would lack the need for regulatory approval, but its specificity limits its translation for SCI.…”