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Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase isozymes by repeated cyanamide administration: Pharmacokinetic‐pharmacodynamic relationships
Author(s) -
Piera Juan Pruñonosa,
Obach Rosendo,
Sagristá Maria Luisa,
Bozal Jorge
Publication year - 1993
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510140508
Subject(s) - cyanamide , aldehyde dehydrogenase , pharmacokinetics , isozyme , pharmacology , chemistry , aldh2 , biochemistry , intraperitoneal injection , enzyme , biology
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 (DI 50 = 0.104 mg kg −1 ) than the high‐ K m isozyme (DI 50 = 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.