Morphine analgesia in cancer pain: role of the glucuronides.

Preclinical data and limited studies in humans have suggested that morphine-6-glucuronide (M6G) has analgesic activity and morphine-3-glucuronide (M3G), contributes adversely to the therapeutic effect of morphine. This open point-prevalence study in 103 patients on oral morphine for cancer-related pain investigated the correlations between morphine doses, metabolites, and the degree of pain relief or toxicity. Morphine, M6G, and M3G were assayed by high-performance liquid chromatography on a single blood sample taken between two and four hours after dose. Pain, analgesia, and toxicity were recorded on numerical and visual analog scales. Patients received a median dose of 60 (range, 10 to 620) mg per day morphine, for a median of 4.1 weeks (range, 0.2 to 46.0 weeks). Ml3G:M6G ratios fell within a narrow range, with a median value of 4.39 (interquartile range, 3.78 to 6.96; range, 2.18 to 14.95). There were no significant correlations between M3G:M6G and morphine dose, or any measure of analgesia. The correlation between plasma concentration and pain score (i.e., better analgesia) was stronger for M6G (r = 0.308, p < 0.01) than morphine (r = 0.197, p = 0.05). These data suggest that M6G contributes significantly to the analgesic potency of oral morphine. No evidence was found for differences in M3G. M6G ratios contributing to analgesia or toxicity.

Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin.

OBJECTIVE: Our objective was to investigate the influence of oxaliplatin on the pharmacokinetics of 5-fluorouracil (5FU) administered in a bolus plus infusional regimen. PATIENTS AND METHODS: All patients had advanced/metastatic colorectal cancer. In study 1, 19 patients were studied after bolus (400 mg/m(2)) plus a 22-hour infusion (600 mg/m(2)) of 5FU/leucovorin in the standard de Gramont regimen or the same regimen with oxaliplatin (85 mg/m(2)) given before 5FU. In study 2, 12 patients were studied for 2 treatment cycles, with 5FU given in a modified de Gramont regimen comprising bolus (400 mg/m(2)) plus a 46-hour infusion (2400 mg/m(2)) of 5FU. During 1 of these cycles, oxaliplatin (85 mg/m(2)) was given before 5FU. RESULTS: The coadministration of oxaliplatin did not significantly alter 5FU area under the plasma concentration-time curve from 0 to 1 hour, area under the plasma concentration-time curve from time 0 to the last time point, or steady-state concentration in either the de Gramont (11.6 +/- 3.8 mg/L x h(-1), 14.9 +/- 4.2 mg x h/L, and 0.17 +/- 0.06 mg/L, respectively, for 5FU alone versus 9.4 +/- 2.6 mg/L x h(-1), 13.3 +/- 2.3 mg x h/L, and 0.16 +/- 0.04, respectively, for 5FU plus oxaliplatin) or modified de Gramont regimens (13.4 +/- 2.2 mg x h/L, 35.4 +/- 4.2 mg x h/L, and 0.46 +/- 0.08 mg/L, respectively, for 5FU alone versus 13.9 +/- 3.3 mg x h/L, 38.1 +/- 7.4 mg x h/L, and 0.53 +/- 0.12, respectively, for 5FU plus oxaliplatin). The inclusion of oxaliplatin coadministration as a covariate in a NONMEM analysis did not result in any change in the objective function or mean values for the following derived parameters: maximum velocity (1590 mg x h(-1)), day 1 Michaelis-Menten constant (7.8 mg x h(-1)), and day 2 Michaelis-Menten constant (11.9 mg x h(-1)). CONCLUSIONS: The coadministration of oxaliplatin in either the standard or modified de Gramont regimen does not significantly affect the pharmacokinetics of 5FU.

The bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine-6-glucuronide.

AIMS: Morphine-6-glucuronide (M6G), one of the active metabolites of morphine, has attracted considerable interest as a potent opioid analgesic with an apparently superior therapeutic index. To date studies have used the intravenous route, which is generally unacceptable in the treatment of cancer related pain. The aim of this study was to define the pharmacokinetics, toxicity and cardio-respiratory effects of three alternative routes of administration of M6G. METHODS: Ten healthy volunteers participated in an open randomized study. Subjects received M6G 2 mg as an intravenous bolus, 20 mg orally, 2 mg subcutaneously and 4 mg by the nebulized route. Pulse, blood pressure, respiratory rate and peak flow rate were monitored and subjective toxicity recorded on rating and visual analogue scales. RESULTS: After i.v. M6G the mean (+/- s.d.) AUC(0,infinity) standardized to a dose of 1 mg was 223 +/- 57 nmol l(-1) h, mean elimination half-life was 1.7 +/- 0.7 h and the mean clearance was 157 +/- 46 ml min(-1). These parameters were virtually identical after subcutaneous administration which had a bioavailability (F(0,infinity)) of 102 +/- 35% (90% CI 82, 117%) and t(max) of 0.5 +/- 0.2 h. The mean bioavailability of nebulized M6G was 6 +/- 2% (90% CI 4, 7%) with a t(max) of 1.2 +/- 0.8 h. Following oral M6G two plasma M6G peaks were seen in 7 of the 10 subjects, the first with a t(max) of 3.1 (+/- 0.9) h. The second peak had a t(max) of 13.4 (+/-5.0) h, started approximately 4 h after dosing, and was associated with the detection of plasma M3G and morphine, suggesting that M6G was significantly hydrolysed in the gut to morphine, which was then glucuronidated following absorption. Although the overall mean bioavailability was 11 +/- 3% (90% CI 9, 12%), confining the analysis to data from the first peak suggested a bioavailability of directly absorbed M6G of only 4 +/- 4%. Apart from a characteristic dysphoria following intravenous and subcutaneous M6G, there was no significant toxicity. CONCLUSIONS: With the minimal toxicity reported in this and previous studies, subcutaneous infusion of M6G may potentially provide clinically useful analgesia for advanced cancer pain. Nebulized M6G is not significantly absorbed via the lungs, and if opiates are shown to have a local effect in the lung, reducing the sensation of breathlessness, then nebulized administration is likely to minimize systemic effects. Oral M6G has poor bioavailability, but is significantly hydrolysed in the gut to morphine, which is subsequently glucuronidated following absorption. This circuitous route accounts for the majority of systemically available M6G after oral administration.