Effects of single and multiple increasing doses of vigabatrin on brain GABA metabolism and correlation with vigabatrin plasma concentration.
The effects of increasing (50-1600 mg/kg/day) doses of vigabatrin (GVG) both as single doses and after 8 or 28 days of treatment have been studied in 19 groups of 10 adult Wistar rats. The parameters studied were brain gamma-aminobutyric acid-transaminase (GABA-T) activity, GABA concentration and L-glutamate decarboxylase (GAD) activity. Single increasing doses of GVG progressively inhibited GABA-T activity, but a residual activity of about 40% was observed with the highest doses. GABA concentration increased in a dose-dependent manner but a ceiling was not reached. GAD activity was slightly inhibited at low doses and stimulated at high ones. When treatment was continued for 8 days, more marked effects of GVG on GABA-T and GABA, a more severe toxicity and higher GVG plasma concentrations were observed. GAD was inhibited instead of stimulated by high GVG doses. After 28 days of treatment the effects of GVG on GABA-T and GABA were similar to those after 8 days. However, toxic effects decreased and lower GVG plasma concentrations were found.


CONCLUSIONS
(a) the more marked brain GABAergic effects observed after 8 days of treatment with GVG may explain the greater anticonvulsant effects observed by others in animals, and (b) GVG plasma concentrations correlate well with changes in brain GABA-T and GABA, and may partly explain changes in the effects of GVG related to the length of treatment.
Valdizán
E M
EM
Clinical Pharmacology Service, M. de Valdecilla University Hospital, Santander, Spain.
Armijo
J A
JA
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000614:Aminocaproates / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000614:Aminocaproates; D000927:Anticonvulsants; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D005968:Glutamate Decarboxylase; D020888:Vigabatrin