Effects of route of administration on dextromethorphan pharmacokinetics and behavioral response in the rat.
D. Wu, S. Otton, Werner Kalow, Edward M. Sellers
Journal of Pharmacology and Experimental Therapeutics September 1, 1995 DOI: 10.1016/s0022-3565(25)10693-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | Dextromethorphan |
| Dose | 30 mg/kg (pharmacokinetics); 60 mg/kg (locomotor activity) |
| Key findings | Route of administration changes dextromethorphan's pharmacokinetics and behavioral effects in rats: intraperitoneal dosing produced more of the metabolite dextrorphan and higher brain dextrorphan levels than subcutaneous dosing, and only intraperitoneal dextromethorphan (60 mg/kg) increased locomotor activity. The authors attribute this to first-pass metabolism. |
Abstract
One of the potential problems of using dextromethorphan as a neuroprotective or anticonvulsant agent is the phencyclidine-like behavioral effects that have been attributed to its major metabolite dextrorphan. Because previous behavioral studies of dextromethorphan have generally failed to consider metabolic conversion to this metabolite, the present studies were conducted to examine the effects of route of administration on dextromethorphan pharmacokinetics and locomotor activity in the rat. The bioavailability of dextromethorphan was 1.3-fold lower and the formation of dextrorphan and other metabolites was 3-fold greater after i.p. injection of 30 mg/kg of dextromethorphan as compared to the s.c. route, indicating substantial effect of first-pass metabolism. Plasma dextromethorphan was correlated with brain dextromethorphan (r = 0.84, P < .001), and the brain/plasma concentration ratio was about 6.5. Plasma-free dextrorphan, but not conjugated dextrorphan, was correlated with brain dextrorphan (r = 0.97, P < .001). Tmax of brain dextrorphan was earlier, and Cmax was higher after i.p. injection of dextromethorphan than s.c. administration (60 min vs. 120 min and 1.0 nmol/g vs. 0.2 nmol/g). Dextromethorphan (60 mg/kg i.p.) increased locomotor activity in the rat 60 min postdose, whereas the same dose of dextromethorphan administered by s.c. injection was without effect. These data demonstrate the route-specific effects on the disposition of dextromethorphan and dextrorphan in rat plasma and brain, as well as the behavioral consequence of the difference.