Morphine-6-glucuronide pharmacokinetics

Stuart-Harris, R., S.P. Joel, P. McDonald, D. Currow, et al., The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine, Br. J. Clin. Pharmacol., 49(3), 207-214, 2000. 

In neonates, and especially in premature infants, the mechanism for glucuronide conjugation is poorly developed. Renal function is also very inefficient. The pharmacokinetics of morphine in neonates is thus markedly different from that in older children and adults. This, together with age-related differences in the development of opioid receptors, may explain their increased sensitivity to morphine. 

Pharmacokinetic properties Codeine (Sindrup and Brosen, 1995) has a good oral bioavailability. The compound is extensively metabolized by O- and N-demethylation followed by glucuronidation. The main metabolites are norcodeine, morphine and hydrocodeine and their glucuronides. There are indications (Yue et al., 1997), that the analgesic effect is reduced in persons with low CYP2D6 activity (poor metabolizers). 

Pharmacokinetic properties Ethylmorphine (Aasmundstad et al., 1995) has a reasonable oral bioavailability. Like codeine, it is metabolized by O- and N-desalkylation, leading to nor-ethylmorphine, morphine, nor-morphine, and the respective glucuronides. 

Lotsch, J. and Geisslinger, G. Morphine-6-glucuronide an analgesic of the future , Clin. Pharmacokinet. 2001, 40, 485-499. 

Lotsch, J., A. Stockmann, G. Kobal, K. Brune, et al., Pharmacokinetics of morphine and its glucu-ronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers, Clin. Pharmacol. Ther., 60(3), 316-325, 1996. 

Zelcer N, van de Wetering K, Hillebrand M, et al. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci USA 2005 102 7274—7279. 

Hunt A, Joel S, Dick G, et al. (1999) Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained-release tablets for cancer pain. J Pediatr 135 47-55. 

Romberg R, Olofsen E, Sarton E, den Hartigh J, Taschner PE, Dahan A. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers Absence of sex differences. Anesthesiology 2004 100 12(h33. 

Figure 11.2 Impact of Mrp3 on the pharmacokinetics of morphine [125], Wild-type mice (closed circle) and Mrp3 (—/—) mice (open circle) received a dose of 15 mg of morphine per kg i. p., and plasma concentrations of morphine (a) and morphine-3-glucuronide (b) were determined at the indicated time points.

J. Lotsch, C. Skarke, H. Schmidt, J. Liefhold, and G. Geisslinger, Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers. Clin Pharmacol Ther 72 151-162 (2002). 

A single 50-mg dose of diclofenac sodium did not have an important effect on the pharmacokinetics of a single 100-mg dose of codeine phosphate in a placebo-controlled crossover study in 12 healthy subjects. There was no effect on the metabolic clearance of morphine, and only a slight (about 5% to 10%) increase in the levels of glucuronide metabolites. In addition, diclofenac did not alter the analgesic effects of codeine as assessed in a cold pressor test (a test in which opioids, but not NSAIDs, are effective). ... 

Penson RT, Joel SP, Roberts M, Gloyne A, Beckwith S, Slevin ML. The bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine-6-glucuronide. Br J Clin Pharmacol 2002 53(4) 347-354. 

F. Stain, M. J. Barjavel, P. Sandouk, M. Plotkine, J. M. Scherrmann, and H. N. Bhargava, /. Pharmacol. Exp. Ther., 274, 852 (1995). Analgesic Response and Plasma and Brain Extracellular Fluid Pharmacokinetics of Morphine and Morphine-6-p-D-Glucuronide in the Rat. 

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