Influence of age on the distribution of morphine and morphine-3-glucuronide across the blood–brain barrier in sheep

Introduction

Neonates are recommended smaller doses of morphine than adults and, accordingly, we hypothesised that the distribution of morphine and its metabolites over the blood–brain barrier differs between these age groups. In addition, neonatal asphyxia, with potentially harmful effects on the brain, in theory, might further affect the pharmacokinetics of substances over the blood–brain barrier.

Methods

During anaesthesia, microdialysis probes were inserted into the brain cortex and in a central vein of 11 exteriorized near-term lambs (127 gestation days) and six nonpregnant adult sheep. Five of these lambs were subjected to 10 minutes of asphyxia through umbilical cord occlusion during delivery. Morphine, 1 mg/kg, was thereafter intravenously administered as a 10 minute constant infusion. Microdialysis and blood samples were collected for up to 360 minutes after morphine administration, and analyzed using liquid chromatography followed by tandem mass spectrometry. Data presented as the mean ± SD.

Results

The morphine unbound drug brain:blood distribution ratio (K_{p, uu}) was 1.19 ± 0.20 and 1.89 ± 0.51 for the sheep and premature lambs without asphyxia, respectively (P = 0.018). The half-lives in the blood and brain cortex, clearance, volume of distribution, and distribution in the brain of unbound drug were all numerically significantly higher in the adult sheep as compared with the premature lambs. The morphine-3-glucuronide K_{p, uu} values were 0.27 ± 0.16 and 0.17 ± 0.15 in sheep and premature lambs (P = NS), indicating a net efflux from the brain in both groups. Induced asphyxia did not affect the results.

Conclusion

The morphine K_{p, uu} was above unity, indicating a net influx of morphine into the brain. In addition, influx was significantly higher in premature lambs than in adult sheep. We interpret this as an active transport of morphine into the brain, which may be counteracted with increased efflux with age. Further, neonatal asphyxia did not change these pharmacokinetic findings. The K_{p, uu} in the sheep was different from the values obtained in humans (0.64), rats (0.49), mice (0.5) and pigs (0.47), where a net efflux of morphine from the brain was observed.