General information is sought concerning clinical pharmacokinetics, analytical method, side-effects

Fråga: General information is sought concerning clinical pharmacokinetics, analytical method, side-effects and indication for therapeutic monitoring of dextromethorphan.

Sammanfattning: O-demethylation of dextromethorphan, the major metabolic pathway, is polymorphic and co-secregated with the hydroxylation of debrisoquine, a traditional probe drug for the CYP2D6 enzyme. Since dextromethorphan is more available and has few adverse effects, it may also be used as a probe drug for debrisoquine hydroxylase.

Svar: CLINICAL PHARMACOKINETICS: Dextromethorphan is well absorbed from the gastrointestinal tract, but the bioavailability is suggested to be low because of extensive first pass metabolism. The drug is mainly eliminated through biotransformation by O-demethylation to dextrorphan, N-demethylation to 3-methoxymorphinan and O- plus N-demethylation to 3-hydroxymorphinan. The O-demethylation is polymorphic and concordant with debrisoquine 4-hydroxylation (1). Peak levels of the drug, which vary remarkably between poor (PM) and extensive (EM) metabolizers of the O-demethylation (<1 ug/l - 8 ug/l), are usually reached within 2.5 hours after a dose of 20 mg. The half-life ranges between 1-2 hours in EMs while it may reach about 40 hours in PMs (2). Dose dependency of the drug metabolism has been reported. Changes of kinetics following kidney impairment are unlikely. Dextrorphan, the O-demethylated metabolite, also has cough suppressant properties.

ANALYTICAL METHODS: Several analytical methods have been developed for the determination of dextromethorphan and its metabolites: GC, HPLC with UV or fluorescence detection, GC-MS and ELISA.

ADVERSE EFFECTS: Adverse effects of the drug appear to be rare and may include dizziness and gastrointestinal disturbances. Excitation, confusion, and respiratory depression may occur after overdosage. The drug has been subject to abuse, but there does not appear to be any evidence of dependence of the morphine type. When giving 120 mg dextromethorphan orally to 29 healthy volunteers, three of the four PMs and nine of the 25 EMs developed adverse effects (3).

CONCENTRATION-EFFECT RELATION and THERAPEUTIC INTERVAL have not been established.

INTERACTIONS: The ingestion of a cough preparation containing dextromethorphan was probably the cause of death in a 26-year-old woman who had been treated with phenelzine 15 mg x4 daily.

PHENOTYPING PROCEDURES: Dose: dextromethorphan hydrobromide 25-40 mg. Urine collection: 8 hours overnight. Samples were stable at 4oC for at least two months. Metabolic ratio: dextromethrophan/dextrorphan; pH-dependent! Antimode: 0.3. There is no effect of smoking, contraceptive use, age or sex on the MR.