Steady-state pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) after intravenous administration of either morphine or M-6-G were determined in healthy volunteers, With a dosing regimen calculated on the basis of data obtained in a first series of experiments in four subjects (morphine: intravenous loading dose of 0.24 mg/kg for 5 minutes and an intravenous infusion of 0.069 mg . kg(-1) . hr(-1) for 4 hours; M-6-G: loading dose of 0.011 mg/kg for 5 minutes and an infusion of 0.006 mg . kg(-1) . hr(-1) for 4 hours), it was possible to yield plasma concentrations of morphine and M-6-G in another four subjects close to predefined targeted levels (35 and 45.5 ng/ml morphine and M-6-G, respectively). This dosing regimen may be used in further pharmacodynamic studies to compare the analgesic effects of morphine and M-6-G, In addition, metabolite kinetics of M-S-G were calculated as a function of time with use of a linear systems approach to the estimation of rate and fraction of morphine glucuronidation to M-6-G.

It has been suggested that morphine-6-glucuronide, a major metabolite of the opioid analgesic morphine, is more potent as an analgesic than the parent drug. This finding appears not to be due to differences in affinity for opioid receptors. Therefore, in the present study the opioid receptor mediated effects of morphine and morphine-6-glucuronide were compared in vitro using electrically induced contractions of isolated guinea-pig ilea in the absence and presence of increasing concentrations of the selective opioid receptor antagonists CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) (mu) and norbinaltorphimine (kappa). The results showed a similar efficacy and potency for morphine and morphine-6-glucuronide and indicated that both compounds act reversibly, mainly at mu-opioid receptors. It is concluded that morphine and its metabolite morphine-6-glucuronide are equipotent at mu-opioid receptors.

The pharmacokinetics of methadone were studied in beagle dogs (n = 4) following intravenous administration of the racemate (0.5 mg/kg) and of the individual (R)-(0.25 mg/kg) and (S)-enantiomers (0.25 mg/kg) using a stereospecific HPLC assay. There was no significant difference between the pharmacokinetic parameters of (R)-methadone and (S)-methadone following administration of the individual enantiomers. Stereoselective differences were evident following administration of the racemate (P values for differences in AUC and CL were 0.01 and 0.046, respectively) and the clearance of the (S)-enantiomer was increased when administered as part of the racemate (316 +/- 81 vs 487 +/- 128 ml/min, P = 0.04). The data suggest that stereoselective disposition including potential enantiomer-enantiomer interactions should be considered in pharmacokinetic-pharmacodynamic studies of (R,S)-methadone.

Determination of methadone (MET) in biological fluids can serve to adjust dosages in patients suffering from cancer pain or participating in methadone maintenance programs. We developed a gas chromatographic assay using nitrogen-phosphorus detection. The method involves a single-step extraction from alkalized plasma, cerebrospinal fluid, or urine into n-hexane/isoamylalcohol (99/1, v/v). Dextropropoxyphene was used as internal standard. Separation was achieved with a silica SE-52-CB column (13 m × 0.25-mm I.D.). The method was validated for the determination of MET in plasma, urine, and cerebrospinal fluid with a quantification limit of 0.5 ng/ mL. The coefficients of variation for within-day and between-day precision were within 10.2 and 14.1%, respectively. Approximately 100 samples can be analyzed by one person in the course of a working day, making the method applicable to routine drug monitoring. The method was demonstrated to be sensitive and accurate for pharmacokinetic studies in plasma, urine, or cerebrospinal fluid.

An enantioselective high-performance liquid chromatographic assay for the quantification of methadone in human and beagle plasma is described. The procedure involves extraction of methadone from alkalized plasma into hexane-isoamyl alcohol (99:1, v/v). Stereoselective separation was achieved with a silica column with covalently bound alpha1-acid glycoprotein (Chiral-AGP) without any derivatization procedure. The detection wavelength was set at 215 nm. Using an internal standard provided reliable control of the extraction procedure as well as quantification of the enantiomers of methadone. The limit of quantification was found to be 2.5 ng/ml. The method was demonstrated to be sufficiently sensitive for stereoselective pharmacokinetic studies of methadone.