Nefopam enantiomers: Preclinical pharmacology/toxicology and pharmacokinetic characteristics in healthy subjects after intravenous administration

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.