Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3- and 6-glucuronide in the human brain.
OBJECTIVE
In animals, central nervous system inflammation increases drug accumulation in the brain partly due to a loss of central nervous system drug efflux transporter function at the blood-brain barrier. To determine whether a similar loss of active drug efflux occurs in humans after acute inflammatory brain injury.


METHODS
Observational human pharmacokinetic study.


METHODS
Medical-surgical-neurosurgical intensive care unit at a university-affiliated, Canadian tertiary care center.


METHODS
Patients with acute inflammatory brain injury, including subarachnoid hemorrhage (n = 10), intracerebral and/or intraventricular hemorrhage (n = 4), or closed head trauma (n = 2) who received morphine intravenously after being fitted with cerebrospinal fluid ventriculostomy and peripheral arterial catheters.


METHODS
We correlated the cerebrospinal fluid distribution of morphine, morphine-3-glucuronide, and morphine-6-glucuronide with the cerebrospinal fluid and plasma concentration of the proinflammatory cytokine interleukin-6 and the passive marker of blood-brain barrier permeability, albumin.


RESULTS
Acute brain injury produced a robust inflammatory response in the central nervous system as reflected by the elevated concentration of interleukin-6 in cerebrospinal fluid. Penetration of morphine metabolites into the central nervous system increased in proportion to the neuroinflammatory response as demonstrated by the positive correlation between cerebrospinal fluid interleukin-6 exposure and the area under the curve cerebrospinal fluid/plasma ratio for morphine-3-glucuronide (r = .49, p < .001) and morphine-6-glucuronide (r = .51, p < .001). In contrast, distribution of morphine into the brain was not linked with cerebrospinal fluid interleukin-6 exposure (r = .073, p = .54). Albumin concentrations in plasma and cerebrospinal fluid were consistently in the normal range, indicating that the physical integrity of the blood-brain barrier was likely undisturbed.


CONCLUSIONS
Our results suggest that central nervous system inflammation following acute brain injury may selectively inhibit the activity of specific drug efflux transporters within the blood-brain barrier. This finding may have significant implications for patients with neuroinflammatory conditions when administered centrally acting drugs normally excluded from the brain by such transporters.
Division of Critical Care Medicine, Department of Medicine and Department of Anesthesia, Queen Elizabeth II Health Sciences Centre and Faculty of Medicine, Halifax, NS, Canada.
Derek J
DJ
Roberts
Kerry B
KB
Goralski
Kenneth W
KW
Renton
Lisa C
LC
Julien
Adam M
AM
Webber
Lekha
L
Sleno
Dietrich A
DA
Volmer
Richard I
RI
Hall
D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D002543:Cerebral Hemorrhage / Q000134:cerebrospinal fluid*; D003422:Critical Care; D004305:Dose-Response Relationship, Drug; D005260:Female; D016489:Head Injuries, Closed / Q000134:cerebrospinal fluid*; D006801:Humans; D015850:Interleukin-6 / Q000134:cerebrospinal fluid; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000134:cerebrospinal fluid*; D012709:Serum Albumin / Q000134:cerebrospinal fluid; D013345:Subarachnoid Hemorrhage / Q000134:cerebrospinal fluid*; D014696:Ventriculostomy
D000701:Analgesics, Opioid; D015850:Interleukin-6; D009022:Morphine Derivatives; D012709:Serum Albumin; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide