Choleretic effect of structural analogs of valproic acid in the rat

A comparison of structure-choleretic activity relationship has been made for several branched- and straight-chain carboxylic acids including valproic acid. Cumulative bile flow was 13.8, 23.8, 29.4 and 14.9 ml/4hr/kg body weight for dimethyl-, diethyl-, dipropyl- (valproic acid), and dibutyl-acetic acid, respectively, after iv administration of approximately equimolar doses (1100 mumoles/kg). Except for dibutylacetic acid, maximal bile flow increased from control rates of 50-60 to 120-140 microliters/min/kg. Administration of higher doses of 2,2-dimethylbutanoic acid and 2-ethylbutanoic acid did not increase maximal bile flow above 125-140 microliters/min/kg but did prolong the duration of choleresis. Maximal and cumulative bile flows increased with length of carboxylic acid chain for 2,2-dimethyl substituted acids (2,2-dimethylacetic acid to 2,2-dimethylbutanoic acid). If the two methyl groups were on C-3 (3-methylbutanoic acid), no change in bile flow was observed. Straight-chain acids from C-5 to C-11 and pent-4-enoic acid did not alter bile flow. Thus, the effectiveness of several branched-chain carboxylic acids as choleretics parallel their ability as anticonvulsants. In contrast, the straight-chain acids which cause central nervous system depression have no choleretic activity.