The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers

J. Lotsch et al., The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers, ANESTHESIOL, 95(6), 2001, pp. 1329-1338
Citations number
Categorie Soggetti
Aneshtesia & Intensive Care","Medical Research Diagnosis & Treatment
Journal title
ISSN journal
0003-3022 → ACNP
Year of publication
1329 - 1338
SICI code
Background Clinical and experimental data suggested a long delay between th e plasma concentration versus time course of morphine-6-glucuronide and the time course of its central opioid effects. This study was aimed at the qua ntification of the transfer half-life (t(1/2,ke0))of this delay. Methods: Pupil size was used as a measure of central opioid effect. Eight h ealthy volunteers (four men, four women) participated In that single-blind randomized crossover study. Median dosages administered intravenously were 0.5 mg morphine as loading dose followed by 10.7 mg given as infusion over a period of 4.7 h, and 10.2 mg M6G as loading dose followed by 39.1 mg M6G given over a period of 3.7 h. The duration of the infusion was tailored to achieve submaximum pupil constriction. The pupil diameter was assessed ever y 20 min for approximately 18 It. Values of t(1/2,ke0) were obtained by sem iparametric pharmacokinetic-pharmacodynamic modeling. Results. The estimated median t(1/2,ke0) of M6G was 6.4 h (range, 2.9-16.2 h), and that of morphine was 2.8 h (range, 1.8-4.4 li). The individual t(1/ 2,ke0) of M6G was always longer than that of morphine. judged by the concen tration at half-maximum effect (EC50) values of the sigmoid pupil size at m aximum constriction (ECmax) model describing concentration-response relatio n, M6G was apparently 22 times less potent than morphine (EC50 = 740.5 nm [ range, 500-1,520 nm] for M6G and 36.2 nm [range, 19.7-43.3 nm] for morphine ). The steepness of the sigmoid E-max model did not significantly differ be tween morphine and M6G (gamma = 1.9 and 2.6, respectively). To produce simi lar pupil effects, the M6G dose had to be 2.8 times greater than the morphi ne dose. Conclusions. The reported numerical value of the t(1/2,ke0) of M6G hi human s obtained after direct administration of M6G is a step toward a complete m odeling approach to the prediction of the clinical effects of morphine. The study raises questions about the high interindividual variability of the t ransfer half-life between plasma and effect site (k(eo)) values and the app arent low potency of M6G.