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

The inhibition of rat hepatic mitochondrial aldehyde dehydrogenase (ALDH) isozymes was studied in apparent steady-state conditions after repeated intra-peritoneal cyanamide administration. The low-K(m) mitochondrial ALDH isozyme was more susceptible to cyanamide-induced inhibition (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 cyanamide administered for the low-K(m) isozyme. The relationships between plasma and liver cyanamide concentrations and the inhibition of high-K(m) ALDH were established by means of the sigmoid I(max) model. The effect of dosing rate on the plasma concentration of cyanamide at apparent steady-state showed non-linearity, indicating that clearance or first-pass metabolism of cyanamide during its absorption after intraperitoneal administration did not remain constant throughout the range of doses studied.