Influence of acetylator phenotype on the pharmacokinetics of a new vasodilator antihypertensive, endralazine.

Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30 +/- 1.08 h for the 5 mg dose and 4.25 +/- 1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC0 infinity) was 18.2% lower (p less than 0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p greater than 0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC0 infinity of the acetylation metabolite (methyltriazolo-endralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p less than 0.01).