Previous Abstract | Next Abstract
Printable Version
Differences in Respiratory Pharmacodynamics after Low and High Dose of Intravenous Morphine-6-Glucuronide (M6G)
Albert Dahan, M.D., Ph.D., Raymonda Romberg, M.D., Elise Sarton, M.D., Ph.D., Hans Bijl, M.D., MSc, Erik Olofsen, MSc
Department of Anesthesiology, Leiden University Medical Center, 2300 RC Leiden, ZH, Netherlands.
Introduction: Morphine-6-glucuronide (M6G) is a metabolite of morphine and like morphine an agonist at the μ-opioid receptor. It was previously shown that at a low intravenous dose (0.2 mg/kg) M6G has a relatively low potency for its respiratory depressant effect (C50 1000-1800 nM) with a short blood effect-site equilibration half-life (1-2 h), relative to its analgesic effect (C50 800 nM and half-life 6 h) and relative to other opioids such a morphine.1,2 In the current study we examined the respiratory pharmacodynamics (PD) of M6G at higher iv doses (0.4 and 0.6 mg/kg) and compared the data with data obtained at 0.2 mg/kg using a PK/PD population approach. The respiratory PD was assesses by measuring the ventilatory response to acute hypoxia over time.

Methods: Twenty-five subjects of either sex participated in this study. Nine subjects received 0.2 mg/kg M6G, eight 0.4 mg/kg M6G, eight 0.6 mg/kg M6G and a final eight received placebo (all given as bolus). Arterial blood samples were obtained for M6G concentrations; acute hypoxic ventilatory responses (AHR) were determined prior to drug administration and at regular intervals for 8 to 24 hours after drug infusion. The data was analyzed using a sigmoid Emax model of the form AHR(t) = AHR0/[1 + (Ce/C50)γ] as well as with a power model of the form AHR(t) = AHR0[1 - 0.5 ⋅ (Ce/C50)γ], where AHR0 is baseline AHR, C50 the steady-state M6G concentration causing 50% reduction of AHR, Ce the effect-site M6G concentration and γ a shape parameter. The data was analyzed using NONMEM, with covariates weight, dose and sex.

Results: Placebo had no systematic effect on AHR. The NONMEM objective function was 20 points lower for the sigmoid Emax model compared to the power model (P < 0.01). We therefore present the results of the PK/PD analysis on the sigmoid model. The PK/PD analysis revealed that dose (0.2 mg/kg versus 0.4 and 0.6 mg/kg) was a significant factor (covariate) on the equilibration half-life and on C50 (P < 0.01) See also the table.

Discussion: We observed distinct M6G pharmacodynamics at low versus high dose. This may be explained by the observation that at low dose, M6G has limited passage through the blood brain barrier (BBB), which is partially related to the active efflux transporter PgP.3,4 The limited respiratory effects at low dose (0.2 mg/kg) may then be of central origin (the low M6G brain concentration causes limited respiratory effect despite greater M6G plasma concentrations) or of peripheral origin (the carotid bodies contain μ-opioid receptors). At high dose (0.4 and 0.6 mg/kg) , the greater M6G potency indicates that M6G accumulates within the brain compartment, possibly related to the saturation of the active efflux-transport of M6G from the brain compartment.

References: 1. Anesthesiology 2004; 99: 788-798; 2. Anesthesiology 2004; 100: 120-1333; 3. Drug Metab Dispos 1997; 25 : 768-771; 4. J Neurochem 2002; 83: 241-248.

Anesthesiology 2004; 101: A1591
PK/PD analysis of M6G respiratory depression
(0.2 mg/kg) (0.4 & 0.6 mg/kg)
half-life (h)1.9 ± 0.4 (*) 8.2 ± 1.7 (*)
AHR0 (L/min/%) 1.0 ± 0.1 (41%)
C50 (nM)860 ± 330 (46%) 420 ± 66 (17%)
γ 2.2 ± 0.6 (*)
Values are population value ± SE (%CV); * = not included in the statistical model