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PubMed2000

In-vivo indices of CYP2D6 activity: comparison of dextromethorphan metabolic ratios in 4-h urine and 3-h plasma.

OBJECTIVES: Dextromethorpan (DM) is widely used as a probe drug to assess in vivo the activity of the cytochrome P450 2D6 (CYP2D6). The aim of the study was to compare metabolic ratios (MRs) of DM to dextrorphan (DEX) in plasma and urine. We examined, separately in urine and plasma, the relationships between the MRs which are based on DEX and those involving the sum of DEX and a secondary metabolite hydroxymorphinan (HM). Furthermore, we compared the MRs in plasma obtained with and without hydrolysis of DEX glucuronides. METHODS: Concentrations of DM and metabolites in urine and plasma were determined by HPLC after a single oral dose of 30 mg DM hydrobromide to 101 healthy Caucasian subjects. Urine was collected over the time interval 0-4 h after the dose and plasma was obtained from 95 subjects 3 h after administration. RESULTS: Six subjects (5.9%) were of poor metaboliser (PM) phenotype (urinary DM:DEX ratio >0.3). A good correlation (r2 = 0.777, P < 0.00001) was observed between the metabolic ratios of DM:DEX in plasma and urine. There was an excellent correlation, both in plasma and urine, between the log-transformed ratios of DM:DEX and of DM to the sum of molar concentrations of DEX and HM (r2 > 0.996, P < 0.00001). Plasma samples of 89 subjects (83 EM and 6 PM) were analyzed without deconjugation of DEX glucuronide also. The correlation between the plasma ratios of DM:DEX based on unconjugated DEX and those involving glucuronide (r2 = 0.793, P < 0.00001) was comparable to that reported by other authors on urine. CONCLUSION: In healthy Caucasian subjects, the MRs of DM to DEX in plasma obtained at 3 h correlated reasonably well with those in urine collected over the time interval 0-4 h after the dose. Nevertheless, repeatability of this plasma index should be determined before its wide use can be recommended. Finally, the interindividual variation in DEX metabolism to HM (catalyzed by CYP3A) contributes only minimally to the interindividual variability of the MRs.

Adult↗
PubMed1996

Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance.

N-Methyl-D-aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusion of either MK-801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furthermore, this prolonged antinociception was completely reversible by naloxone (10 mg/kg, i.p.). Doses of MK-801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, respectively) revealed different profiles of effects, however, on locomotor activity and naloxone-precipitated abstinence/withdrawal symptoms. With regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK-801, but not rats having received morphine sulfate and DM, displayed a reliable and striking increase in locomotor activity as compared with rats having received morphine alone. With regard to naloxone-precipitated withdrawal symptoms, continuous (48 h) subcutaneous co-infusion of either MK-801 (0.01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone-precipitated hyperalgesia as compared with rats infused with morphine alone. MK-801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone-precipitated withdrawal symptoms (teeth chattering, jumping and wet dog shakes). The effects of MK-801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK-801 and morphine. These results extend previous observations by showing that the prolonged antinociception observed following co-administration of morphine and an NMDA antagonist is completely naloxone-reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor-mediated effect. The different profiles of side effects associated with MK-801 and DM, however, suggest that (1) attenuation of naloxone-precipitated withdrawal symptoms by MK-801 may be an artifact of toxicity, and (2) DM may prove clinically useful for the prevention of morphine tolerance, given its lack of observable side effects when administered concurrently with morphine to rodents.

Animals↗