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

Background and purpose: The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied. Experimental approach: Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg.kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K-p,K-uu) and unbound drug volume of distribution in brain (V-u,V-brain) were estimated. Key results: Morphine K-p,K-uu was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V-u,V-brain measurements were higher in sheep than in premature lambs. The M3G K-p,K-uu values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups. Conclusions and implications: The morphine K-p,K-uu was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed. British Journal of Pharmacology (2009) 157, 1085-1096; doi: 10.1111/j.1476-5381.2009.00242.x; published online 11 May 2009