Effect of route of administration on the pharmacokinetic behavior of enantiomers of nefopam and desmethylnefopam

Nefopam hydrochloride is a non-narcotic analgesic used parenterally and orally as a racemic mixture for the relief of postoperative pain. However, no information is presently available on the oral kinetics of (+) and (-) nefopam in humans. Also, nefopam is metabolized by N-demethylation but it is not known whether the desmethylnefopam enantiomers (DES1 and DES2) are present in plasma following intravenous (I.V.) or oral administration of parent drug. To address these issues, 24 healthy white male subjects received two treatments using a double-blind, placebo-controlled crossover design: oral administration of 20 mg nefopam hydrochloride solution or a placebo solution on a sugar cube, simultaneously with a continuous infusion of 20 mg nefopam hydrochloride or placebo infusion. A chiral assay using LC-MS was developed for the simultaneous determination of both enantiomers of the parent drug and its metabolite in plasma and urine. Following I.V. administration, the kinetics of (+) and (-) nefopam could be fitted to a bi-exponential equation but exhibited no stereoselectivity. Both enantiomers had large clearances (53.7 and 57.5 L/hr) and volumes of distribution (390 and 381 L) and half-lives around 5 hours. Following oral administration, (+) and (-) nefopam were rapidly absorbed with bioavailabilities of 44% and 42%, respectively, probably due to a first-pass effect. After I.V. administration, the enantiomers of desmethylnefopam exhibited lower concentrations and longer half-lives (20.0 h for DES1 and 25.3 h for DES2) relative to nefopam enantiomers. Following oral administration, desmethylnefopam enantiomers' plasma concentrations peaked earlier and higher than after I.V. administration (P < 0.05). Following I.V. and oral administration, desmethylnefopam enantiomers showed stereoselectivity in AUC and Cmax values. Urinary excretion of parent and metabolite enantiomers was less than 5% of dose. This study shows that desmethylnefopam enantiomers can contribute to the analgesic effect of racemic nefopam only when it is administered orally.