The bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine-6-glucuronide.
OBJECTIVE
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.
Penson
Richard T
RT
Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE.
Joel
Simon P
SP
Roberts
Michael
M
Gloyne
Anna
A
Beckwith
Stephen
S
Slevin
Maurice L
ML
D000280:Administration, Inhalation; D000284:Administration, Oral; D000328:Adult; D017109:Akathisia, Drug-Induced; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009022:Morphine Derivatives / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D009330:Nebulizers and Vaporizers
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide