INHIBITION OF RAT HEPATIC MITOCHONDRIAL ALDEHYDE DEHYDROGENASE ISOZYMES BY REPEATED CYANAMIDE ADMINISTRATION - PHARMACOKINETIC-PHARMACODYNAMIC RELATIONSHIPS

The inhibition of rat hepatic mitochondrial aldehyde dehydrogenase (AL DH) isozymes was studied in apparent steady-state conditions after rep eated intra-peritoneal cyanamide administration. The low-K(m) mitochon drial ALDH isozyme was more susceptible to cyanamide-induced inhibitio n (DI50 = 0.104 mg kg-1) than the high-K(m) isozyme (DI50 = 8.52 mg kg -1), with almost complete inhibition occurring at 0.35 mg kg-1 total c yanamide administered for the low-K(m) isozyme. The relationships betw een plasma and liver cyanamide concentrations and the inhibition of hi gh-K(m) ALDH were established by means of the sigmoid I(max) model. Th e effect of dosing rate on the plasma concentration of cyanamide at ap parent steady-state showed non-linearity, indicating that clearance or first-pass metabolism of cyanamide during its absorption after intrap eritoneal administration did not remain constant throughout the range of doses studied.