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


METHODS
Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg x 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,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated.


RESULTS
Morphine K(p,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,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups.


CONCLUSIONS
The morphine K(p,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.
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala SE-751 24, Sweden.
J
J
Bengtsson
P
P
Ederoth
D
D
Ley
S
S
Hansson
I
I
Amer-Wåhlin
L
L
Hellström-Westas
K
K
Marsál
C-H
CH
Nordström
M
M
Hammarlund-Udenaes
D000367:Age Factors; D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D009020:Morphine / Q000378:metabolism* / Q000494:pharmacology; D009022:Morphine Derivatives / Q000378:metabolism* / Q000494:pharmacology; D012756:Sheep; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D009022:Morphine Derivatives; D009020:Morphine; C018108:morphine-3-glucuronide