Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers.
OBJECTIVE
After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers.


METHODS
The study was conducted accordingly to a nonblinded, randomised, balanced three-way crossover design in eight healthy male subjects. The subjects received 200 mg oral M6G, 50 mg oral M6G and 30 mg oral morphine. Blood samples were collected until 72 h after M6G administration and until 9 h after morphine administration. Paracetamol and sulfasalazine were coadministered with M6G as markers for the gut contents reaching the duodenum and colon, respectively.


RESULTS
The plasma concentration peaks of M6G were seen at 4.0 (2.0-6.0) and 18 (12.0-24.0) h after 200 mg M6G and at 3.5 (2.0-6.0) and 21.3 (10.0-23.3) h after 50 mg M6G, which was in agreement with previously published results. The K(M6G_abs)/K(M6G_M6G) ratio was found to be 10.


CONCLUSIONS
The pharmacokinetic profile of M6G after oral administration was confirmed and with the presence of M3G and morphine in plasma after oral administration of M6G, proof seems to be found of the constant and prolonged absorption of M6G. The K(M6G_abs)/K(M6G_M6G) ratio of 10 indicates that the second absorption peak of M6G consists of approximately 10 times more absorbed M6G than reglucuronidated M6G. However, further studies are required to determine the precise kinetics of the second absorption peak.
Villesen
Hanne H
HH
Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
Kristensen
Kim
K
Hansen
Steen H
SH
Jensen
Niels-Henrik
NH
Skram
Ulrik
U
Christrup
Lona L
LL
D000042:Absorption; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D006801:Humans; D006868:Hydrolysis; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide