Limited Phase I Study of Morphine-3-Glucuronide

The toxicity of morphine-3-glucuronide (M3G) has been investigated in an open, uncontrolled, single-blinded, single dose study over a limited range of doses. Three cohorts each of three healthy volunteers received 7.5, 15, and 30 mg/70 kg intravenous (IV) M3G. Blood sampling was undertaken for the following 24 h. Subjective toxicity was recorded on visual analogue scales and plasma M3G concentrations measured by a specific HPLC assay. Virtually no effects and no change in cardiovascular or respiratory parameters were seen. The pharmacokinetics fitted a two-compartment model. The mean elimination half-life (± S.D.) of M3G was 1.66 (± 0.47) h. Mean AUC standardized to a dose of 1 mg/70 kg was 228 (± 62) ηmolL−1 · h. Mean M3G clearance was 169 (± 48) mLmin−1 and the mean volume of distribution was 23.1 (± 4.8) liters. At the doses investigated there were no clear neuroexcitatory effects, no opioid effects, and the pharmacokinetics were very similar to those of morphine-6-glucuronide (M6G). © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1810–1816, 2001