Hydralazine kinetics after single and repeated oral doses

Abstract

In reports on hydralazine kinetics plasma hydralazine levels have been measured with nonspecific assay techniques. The techniques used also include acid-labile hydralazine metabolites and therefore markedly overestimate hydralazine levels. We have developed specific, sensitive assay methods for the measurement of hydralazine and its major plasma metabolite, hydralazine pyruvic acid hydrazone (HPH). By these methods, we determined hydralazine and HPH kinetics after single and repeated oral doses of hydralazine in eight hypertensive patients. Hydralazine bioavailability in the fast acetylator group (9.5% single dose, 6.6% repeated doses) and in the slow acetylator group (31.3% single dose, 39.3% repeated doses) was phenotype dependent. Peak plasma levels were lower than those reported with nonspecific assays: 0.32 microM for the single dose and 0.14 microM for repeated doses in the fast acetylator group and 1.03 microM for the single dose and 0.96 microM repeated doses in the slow acetylator group. There was no alteration in kinetics and no cumulation in plasma on repeated administration. HPH plasma levels were proportional to those of hydralazine in both acetylator groups and were 2.5 to 4 times as high as those of hydralazine. Elimination half-lifes were phenotype independent, ranging from 4 to 6 hr. HPH cumulated in the rapid but not in the slow acetylator group after repeated doses of hydralazine.

Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins

“…Furthermore, as incomplete inhibition of LDL modification appears to be sufficient to prevent scavenger receptor recognition and particle uptake, it is possible that even low levels of these carbonyl-scavenging compounds may be beneficial. After oral dosing in humans hydralazine and metformin can reach micromolar concentrations and aminoguanidine concentrations of tens of micromoles [32,[45][46][47], levels that are considerably in excess of those of the reactive aldehydes (see above). It is therefore conceivable that these compounds may act as efficient scavengers of reactive aldehydes in vivo, especially as it has been demonstrated that equimolar levels of these drugs are sufficient to induce significant protection against aldehyde-mediated LDL modification.…”

Pharmacogenetics of the arylamine N-acetyltransferases

“…111 This difference appeared to be due to a change in the bioavailability of the drug which decreased from 33% in slow acetylators to less than 10% in rapid acetylators. 112 A more common consequence of the polymorphic acetylation of therapeutic agents is an increase in the frequency and severity of side-effects associated with either the rapid or slow phenotype (Table 3). These adverse effects often arise as the result of a shift in the metabolic pathways responsible for the activation and detoxification of the drug.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…In fast acetylators, the oral availability of hydralazine is 7 to 16%, reflecting presystemic metabolism by NAT2. Slow acetylators have higher oral availability (30 -40%), and hydralazine pyruvic acid hydrazone is the main plasma metabolite, resulting from reaction with pyruvic acid in plasma (Reece et al, 1980;Shepherd et al, 1980). The AUC of hydralazine is ϳ3-fold higher in slow acetylators, and this may increase to 6-to 7-fold higher with multiple dosing (Reece et al, 1980;Shepherd et al, 1980).…”