Altered brain exposure of morphine in experimental meningitis studied with microdialysis.
BACKGROUND
During pathologic conditions such as meningitis and traumatic brain injury the function of the blood-brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed.


METHODS
Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg(-1) was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated.


RESULTS
The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) (P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis.


CONCLUSIONS
This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.
Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden. Karin.Tunblad@farmbio.uu.se
K
K
Tunblad
P
P
Ederoth
A
A
Gärdenfors
M
M
Hammarlund-Udenaes
C-H
CH
Nordström
D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004058:Diffusion; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000378:metabolism; D006207:Half-Life; D007262:Infusions, Intravenous; D007601:Jugular Veins / Q000378:metabolism; D008581:Meningitis / Q000378:metabolism*; D017551:Microdialysis; D008991:Monitoring, Physiologic; D009020:Morphine / Q000097:blood / Q000493:pharmacokinetics*; D009294:Narcotics / Q000097:blood / Q000493:pharmacokinetics*; D009778:Occipital Lobe / Q000378:metabolism; D013552:Swine; D014160:Transducers, Pressure
D009294:Narcotics; D009020:Morphine