PHARMACOKINETIC ANALYSIS AND ANTIEPILEPTIC ACTIVITY OF 2 NEW ISOMERS OF N-VALPROYL GLYCINAMIDE

Valproyl glycinamide (TV 1901-VPGD) is a new antiepileptic drug, which is currently undergoing clinical trials. The present study explored t he pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of two new isomers of valproyl glycinamide: valnoctyl g lycinamide (VCGD) and diisopropylacetyl (DIGD). Both VCGD and DIGD sho wed anticonvulsant activity and a safety margin in mice similar to tho se of VPGD. Following iv administration (556 mg) to six dogs, VCGD had a clearance (Cl) value of 3.8+/-1.1 L h(-1) (mean +/- SD), a volume o f distribution (V-ss) of 15+/-2 L and a half-life (t(1/2)) of 1.9+/-0. 3 h. DIGD had Cl, V-ss, and t(1/2) values of 10+/-0.8 L h(-1), 19+/-3 L, and 1.6+/-0.2 h, respectively. Neither VCGD nor DIGD operated as ch emical drug delivery systems (CDDSs) of glycine, valnoctic acid, or di isopropyl acetic acid and both showed antiepileptic profiles different from that of valproic acid (VPA). Both glycinamides were biotransform ed to their glycine analogues with similar fractions metabolized (f(m) ): 59+/-5% (VCGD) and 62+/-15% (DIGD). The two glycine metabolites, va lnoctyl glycine (VCGA) and diisopropylacetyl glycine (DIGA), were also administered to the same dogs in order to calculate the above f(m) va lues. Both VCGA and DIGA had higher Cl and lower V-ss values than VCGD and DIGD and therefore their mean t(1/2) values were 0.43+/-0.02 and 0.30+/-0.07 h, respectively. VCGA and DIGA were excreted mainly intact in the urine, with fractions excreted unchanged (f(e)) of 60+/-9 and 55+/-7%, respectively. The improved pharmacokinetic profile of VCGD an d DIGD relative to their glycine analogues may explain the similarity of their anticonvulsant activity to that of valproyl glycinamide. The current study demonstrates the benefit of the structure-pharmacokineti c-pharmacodynamic relationship (SPPR) approach in developing and selec ting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity but also on its improved pha rmacokinetic profile. (C) 1997 by John Wiley & Sons, Ltd.