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-Km mitochondrial ALDH isozyme was more susceptible to cyanamide-induced inhibition (DI50 = 0.104 mg kg-1) than the high-Km isozyme (DI50 = 8.52 mg kg-1), with almost complete inhibition occurring at 0.35 mg kg-1 total cyanamide administered for the low-Km isozyme. The relationships between plasma and liver cyanamide concentrations and the inhibition of high-Km ALDH were established by means of the sigmoid Imax 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.
Pruñonosa Piera
J
J
Department of Biochemistry and Physiology, Faculty of Chemistry, University of Barcelona, Spain.
Obach
R
R
Sagristá
M L
ML
Bozal
J
J
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D003484:Cyanamide / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D007527:Isoenzymes; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase