In vitro effects of the novel anti-epileptic agent vigabatrin on alanine aminotransferase and aspartate aminotransferase activities in rat serum.
The in vitro effects of vigabatrin (CAS 60643-86-9, MDL 71,754) on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were examined in rat serum. Initially, vigabatrin (30-100 micrograms/ml) produced a concentration-dependent decrease in ALT activity at 100 micrograms/ml or more after 15 min incubation with the rat serum. AST activity, in contrast, was unaffected by concentrations up to 1,000 micrograms/ml. Next, treating the rat serum with vigabatrin (30-300 micrograms/ml) for up to 5 h produced a concentration- and time-dependent decrease in ALT activity. On the other hand, a decrease in AST activity was observed only after incubation with the highest concentration of vigabatrin for 3 h or more. Finally, an investigation was made on the antagonistic effect of L-alanine, a natural substrate for ALT, on the vigabatrin-induced decrease in ALT activity to elucidate possible mechanisms underlying the inhibitory effect of vigabatrin on ALT activity. L-alanine, depending on its concentration, countered the effects of vigabatrin (100 micrograms/ml) at a 10- or 100-fold higher molar ratio than vigabatrin. These findings suggest that vigabatrin favorably decreases ALT activity by blocking the L-alanine binding site of enzymes.
Okumura
H
H
Development Laboratories, Marion Merrell Dow, Osaka, Japan.
Omote
M
M
Takeshita
S
S
D000409:Alanine / Q000494:pharmacology; D000410:Alanine Transaminase / Q000037:antagonists & inhibitors* / Q000097:blood; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000037:antagonists & inhibitors* / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000927:Anticonvulsants; D005680:gamma-Aminobutyric Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020888:Vigabatrin; D000409:Alanine