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Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1‐methyl‐1‐cyclohexanecarboxylic acid
Author(s) -
Liu MeiJen,
Pollack Gary M.
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.2510140406
Subject(s) - chemistry , pharmacokinetics , cyclohexanecarboxylic acid , enterohepatic circulation , carboxylic acid , metabolism , urine , valproic acid , pharmacology , benzoates , chromatography , biochemistry , organic chemistry , biology , neuroscience , epilepsy
The pharmacokinetics of valproic acid (VPA) and three structural analogs, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1‐methyl‐1‐cyclohexanecarboxylic acid (MCCA), were examined in female Sprague‐Dawley rats. All four carboxylic acids evidenced dose‐dependent disposition. A dose‐related decrease in total body clearance was observed for each test compound, suggesting the presence of saturable elimination processes. Furthermore, the apparent volume of distribution for these compounds was, with the exception of CCA, dose‐dependent, indicating that binding to proteins in serum and/or tissues may be saturable. Both VPA and MCCA exhibited enterohepatic recirculation, although the degree of recirculation appeared to be dose‐ and compound‐dependent. Significant quantities of both VPA and MCCA were excreted in the urine as base‐labile conjugates, presumably representing glucuronides. In contrast, OA and CCA were not excreted in the urine as base‐labile conjugates and did not evidence enterohepatic recirculation. CCA displayed apparent Michaelis‐Menten kinetics, although the calculated K m was dose‐dependent. The results suggest that relatively minor changes in chemical structure have a marked influence on the metabolism and disposition of low molecular weight carboxylic acids.