FASEB J. 2013
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Inflammation-induced alterations in drug disposition during
inflammatory conditions such as infection and surgery are common and may lead to
altered drug responses and/or toxicities. Animal studies have shown that inflammation
alters drug disposition into the brain, which has been attributed to regulatory effects of
proinflammatory cytokines on blood-brain barrier drug efflux transporters, such as the
ATP-binding cassette transporter P-glycoprotein. It is not known if such cytokine-bloodbrain barrier drug transporter interactions occur and are important in humans.
To advance knowledge in this area by investigating the effects of
inflammation on drug distribution across the blood-brain barrier in humans. Specifically,
the goal was to determine the effects of surgery-induced inflammation on morphine
distribution across the blood-brain barrier.
Patients undergoing elective aortic surgery that received morphine in their
standard treatment were divided in two groups: cardiopulmonary bypass, CPB (n = 18)
and non-CPB (n = 18) group, based on the surgery they received. Blood and
cerebrospinal (CSF) samples were collected before, during and after the surgery. Plasma
and CSF morphine, morphine-3 and morphine-6 glucuronide concentrations were
determined by mass-spectrometry. Cytokines were quantified with Q-plex multiplex
ELISA to characterize the surgical inflammatory response and albumin was measured in
both plasma and CSF samples as a marker of passive blood-brain barrier permeability.
The plasma Cmax and area under the curve from 0 to 24 h (AUC0-24h) of
interleukin-6 (IL-6), a known regulator of blood-brain barrier drug transporters were
higher (P < 0.05) in the CPB group (1045 ± 1421 pg/ml and 9299 ± 12940 pg/ml*h) than
in the non-bypass group (162.0 ± 135.4 pg/ml and 2069 ± 2053 pg/ml*h) indicating that
individuals receiving CPB had a more robust systemic inflammatory response. The
CSF/plasma morphine AUC0-24h ratio was significantly lower in the CPB than in nonCPB groups (1.09 ± 0.52 and 2.65 ± 1.97, respectively). Albumin CSF/Plasma ratio was
increased in the CPB group following surgery, indicating possible increase of blood-brain
: CSF morphine exposure is lower in individuals undergoing aortic
aneurysm with CPB. This effect may be due to IL-6-mediated changes in blood-brain
barrier drug uptake or efflux transporter function and may be one explanation for altered
drug effect in the critically ill patient.
Altered drug disposition can cause adverse drug reactions (ADRs),
which will lead to higher mortality, prolonged hospitalization and increased medical
costs. Patients with cardiovascular diseases are particularly at high risk of ADRs and
opioid analgesics are frequently associated with ADRs. By studying patients receiving
cardiac surgeries and morphine, we have obtained a better understanding of morphine’s
distribution across blood-brain barrier under inflammatory conditions, which may help
reduce ADRs in future clinical practice.