Relationship between platelet and brain GABA transaminase inhibition by single and multiple doses of vigabatrin in rats.
Vigabatrin (gamma-vinyl-GABA, GVG) is an inhibitor of brain GABA transaminase (GABA-T) that also inhibits platelet GABA-T in rats and humans. We have compared the effects of single and multiple doses of GVG on both enzymes in 19 groups of 10 adult male Wistar rats, treated with increasing GVG doses (0-1,600 mg/kg/day) for 1, 8, and 28 days. The platelet GABA-T was more sensitive to the inhibitory effects of GVG than the brain enzyme was especially with low dosages of GVG. After 8 days of treatment, higher GVG plasma levels and a higher inhibition of both enzymes were shown. However, after 28 days, lower GVG plasma levels and similar inhibition of both enzymes compared to the eighth day were found. Correlations between platelet and brain GABA-T for individual rats were statistically significant after 1 day (r = 0.40, p less than 0.01) but not after 8 and 28 days of treatment because of the total inhibition of platelet GABA-T and only partial inhibition of brain GABA-T. We concluded the following: (a) platelet GABA-T is more inhibited than brain GABA-T when low doses of GVG are used and (b) multiple doses reach a higher inhibition of both enzymes than single doses, which could be explained by an increase in GVG concentrations.
Clinical Pharmacology Service, M. de Valdecilla, University Hospital, Santander, Spain.
E M
EM
Valdizán
J A
JA
Armijo
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000614:Aminocaproates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D020888:Vigabatrin
D000614:Aminocaproates; D000927:Anticonvulsants; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin