Disposition and pharmacokinetics of cadralazine and individual metabolites in man

Abstract

The absorption, biotransformation and elimination of the antihypertensive drug cadralazine, 2-(3-[6-(2-hydroxypropyl)ethylamino]pyridazinyl)-ethylcarbazate , have been studied in two healthy male volunteers, following single 20 mg oral doses of the 14C-labelled preparation. Absorption was rapid and complete. In plasma total 14C-compounds reached maximum levels of 395 and 312 ng/g after 0.5 and 1.5 h in subject A and B, respectively. The levels rapidly declined to 3 and 6 ng/g after 24 h. Unchanged cadralazine constituted the major fraction, 72%, of the integrated plasma concentration (AUC, 0-24 h) of total radioactivity. As determined by an isotope dilution technique, about 1% of the AUC of plasma-14C was attributable to a pharmacologically active hydrazino-metabolite (IV) formed by decarbethoxylation and 2% to the acetylation product of the latter (V). Excretion of the radioactivity occured predominantly by the kidneys, 91 and 94% within 0-24 h in subject A and B. After 96 h 94 and 99% of the dose were found in the excreta. In the 0-48 h urine 73% of total 14C consisted of unchanged drug. The hydrazino-metabolite (IV) accounted for about 2% of urinary radioactivity, and two secondary products of the same pathway (II, V) for another 2%. Products of N-dealkylation (VI, VII) and C-oxidation (VIII) constituted together another 5%.