Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid.
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 Km 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.
Division of Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360.
M J
MJ
Liu
G M
GM
Pollack
D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D002210:Caprylates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D003509:Cyclohexanecarboxylic Acids / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D000959:Antihypertensive Agents; D002210:Caprylates; D003509:Cyclohexanecarboxylic Acids; C027655:1-methylcyclohexanecarboxylic acid; D014635:Valproic Acid; C044895:cyclohexanecarboxylic acid; C031492:octanoic acid