Gg. Mather et al., Nefopam enantiomers: Preclinical pharmacology/toxicology and pharmacokinetic characteristics in healthy subjects after intravenous administration, CHIRALITY, 12(3), 2000, pp. 153-159
Nefopam (NEF) is a potent analgesic compound administered as a racemic mixt
ure. Previous in vitro and in vivo studies with nefopam enantiomers have sh
own that (+)nefopam [(+)NEF] is substantially more potent than (-)nefopam [
(-)NEF]. Differences between enantiomers have also been suggested in metabo
lic studies in vitro. The impact of these differences in vivo is not known
because there is little or no information on the relative plasma concentrat
ions of the enantiomers or on their kinetics. In this study, individual ena
ntiomers of nefopam were synthesized and examined for acute toxicity in mal
e and female rats and mice. Pharmacologic properties of enantiomers were ex
amined using in vitro binding assays and antinociceptive tests in rats and
mice. Additionally, a pharmacokinetic study was conducted in human voluntee
rs. Subjects were administered 20 mg nefopam as Acupan(R) either as a 5- or
20-min intravenous infusion. In a control phase, subjects were administere
d only vehicle. Blood samples were collected through the following 24 h. Pl
asma samples were analyzed for individual enantiomers using a chiral assay
developed for this purpose. The pharmacologic differences of previous studi
es were confirmed in receptor binding assays and in the hot plate and the f
ormalin tests in mice. Neither enantiomer demonstrated substantial activity
in the tail flick test in rats. No significant differences were revealed b
etween LD50 values of nefopam enantiomers after oral or intravenous adminis
tration in male and female rats or mice. There were no significant differen
ces in AUC(0-infinity), C-max, or half-life between enantiomers following i
ntravenous administration. Based on these findings, there is currently no c
ompelling rationale to justify administering or monitoring individual enant
iomers. Chirality 12:153-159, 2000. (C) 2000 Wiley-Liss, Inc.