Inter-individual variation in the metabolism of dextromethorphan

Abstract

After ingestion of 25 mg of dextromethorphan-HBr in 12 healthy volunteers, the plasma concentrations of dextromethorphan and conjugated dextrorphan as well as the cumulative excretion of dextromethorphan and the conjugated metabolites dextrorphan, 3-hydroxymorphinan and 3-methoxymorphinan in the urine within 48 h were determined. Based on the results, the volunteers were divided into 3 groups. Conjugated dextrorphan was prevailing in the plasma and urine of the 6 volunteers of Group 1, whereas no unmetabolized dextromethorphan was detectable in the plasma and only slight traces of it in the urine. The plasma elimination of dextrorphan has a half-life of 1.2−2.2 h. After 48 h an average amount of 86% of the dosage was excreted. The second group comprised those volunteers whose plasma contained clearly determinable concentrations of unmetabolized dextromethorphan (maxima: 11.7−14.4 ng/ml) besides dextrorphan, and whose dextrorphan plasma level curves showed an additional βS-phase with half-lives of about 6 h. The urine of these volunteers contained an average of 2.6% of the dosage, i.e. approximately 20 times as much dextromethorphan as the volunteers of Group 1. The cumulative excretion in the urine of 74% was lower than that of the first group. An individual case that is already reported in the literature was also classified into this second group (Barnhart, 1980). Compared with other volunteers the remaining 3 volunteers showed the most obvious deviations: only unchanged dextromethorphan and no dextrorphan could be detected in the plasma, whereby an increased plasma elimination half-life of approximately 45 h was found. Moreover, the excretion in the urine was slower (approximately 20% of dose in 48 h) and unmetabolized dextromethorphan was, with more than 50% of the excreted amount, the main excretion product. The 12 volunteers investigated had been selected after a preliminary trial from a population of 46 persons. Based on the results presented, the frequency of the different metabolization occurring in this population could be subsequently determined s approximately 6% and 13% for Groups 2 and 3, respectively.