Diffusion of morphine-6-beta-D-glucuronide into the neonatal guinea pig brain during drug-induced respiratory depression.
Morphine-6-beta-D-glucuronide (M6G) is an active metabolite of morphine. In a previous study, M6G depressed respiration in the neonatal guinea pig, becoming more potent with aging, a finding that is confirmed in the current study. After s.c. injection, M6G is absorbed into plasma, crosses the blood-brain barrier and is present in the central nervous system at the time of maximal M6G-induced ventilatory depression. No hydrolysis of M6G to morphine is detected in either plasma or brain tissue by high-performance liquid chromatography. About 30% more M6G is in plasma in 3-day-old than in 7-day-old pups after drug administration (P < .05). Mean brain concentrations of M6G are 12% higher on day 3 than day 7, but the difference is not statistically significant. Brain-to-plasma ratios of M6G do not differ after 5 or 15 mg/kg of M6G or with age (mean ratio = 0.037). Brain drug concentration is a linear function of plasma drug levels (r2 = 0.84), suggesting M6G crosses the blood brain barrier by diffusion. Differential systemic absorption or central nervous system distribution of M6G cannot explain enhanced respiratory depression with aging. Morphine-3-beta-D-glucuronide (M3G) also crossed the blood-brain barrier, but is less permeable than M6G (mean brain-to-plasma ratio = 0.022). Contrary to reports in the literature, M3G at a dose of 75 mg/kg, does not stimulate respiration in this study. Morphine administration to neonatal guinea pigs produces measurable plasma and brain levels of M6G and M3G.(ABSTRACT TRUNCATED AT 250 WORDS)
Murphey
L J
LJ
Department of Pharmacology, School of Medicine, Oregon Health Sciences University, Portland.
Olsen
G D
GD
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D004058:Diffusion; D006168:Guinea Pigs; D009020:Morphine / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000493:pharmacokinetics*; D012119:Respiration / Q000187:drug effects*; D012995:Solubility
D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide