A comparison of the effects of lamotrigine on neuroma-induced action potential firing and normal behaviour in rat: implications for establishing a pre-clinical 'therapeutic index'.
The effects of lamotrigine on rat neuroma and behavioural paradigms were evaluated to determine a pre-clinical therapeutic index. Lamotrigine blocked neuroma-induced burst pattern firing at a free plasma concentration of 13.7+/-1.7 microM (n=5). Oral dosing of lamotrigine (50-200 mg/kg) had no significant effects on behaviour but measurements of plasma concentrations of free drug showed non-linear oral absorption and lower than predicted drug levels (5-27 microM). Given intravenously (10-100 mg/kg), lamotrigine did affect behaviour at a free plasma concentration of 42.0 microM (n=2). By comparing free plasma concentrations, a therapeutic index of 3 was calculated, which is lower than published data based on comparing oral doses. We propose that a therapeutic index should only be derived with reference to plasma drug concentrations to prevent non-linear or incomplete drug absorption from confounding accurate estimation.
Butler
P
P
Discovery Biology, PGRD, Kent, CT13 9NJ, Sandwich, UK.
Gardiner
J C
JC
Loftus
J P
JP
Karran
E
E
Roffey
S J
SJ
Gupta
P
P
Pryke
J G
JG
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D000077213:Lamotrigine; D008297:Male; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D009463:Neuroma / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D014227:Triazines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine