this issue, we investigated the CNS distribution of reference com- pounds with ... J. Brazier, PhD, MDS Pharma Services/University of Montreal, St-. Laurent ...
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CLINICALPHARMACOLOGY& THER,M)EUTICS FEBRUARY2003
American Societyfor Clinical Pharmacology and Therapeutics
PII-71
PII-73
BRAIN AND SPINAL CORD DISTRIBUTION OF REFERENCE COMPOUNDS WITH VARYING DEGREES OF CNS PENETRATION 1N A RAT MODEL OF CEREBRAL INFLAMMATION. S. Dantrev, PhD, D. Projean, BPharm, M. Roumi, PhD, J. Ducharme, PhD, AstraZeneca R&D Montreal, Universit6 de Montrdal, Montreal, Canada. In humans, conditions associated with cerebral inflammation, such as migraine or meningitis, can disrupt blood brain barrier integrity, which in turn may affect the entry of drugs into the CNS. To address this issue, we investigated the CNS distribution of reference compounds with varying degrees of CNS penetration in a rat model of cerebral inflammation induced by the intracerebroventricular (icy) administration of 2.4 p~g of lipopolysaccharides (LPS). Three and half hours later, LPS-treated or naive rats received 10 ixmol/kg iv of atenolol, quinidine or imipramine (n=5/group). At 30 rain, rats were sacrificed and a blood sample, brains (BR) and spinal cords (SC) were collected. Drug levels were measured by LC-MS. Atenolol, quinidine and imipramine were selected as representative compounds of low, medium and high CNS penetration, as evidenced by naive rat BR or SC to plasma ratios of d0.1, 1 and >40, respectively. In LPS-treated rats, atenolol remained peripherally restricted (CNS levels 2 4 nmol/g). In contrast, CNS levels of quinidine were significantly increased (4-fold vs nfffve rats). This suggests that icy LPS administration does not affect the CNS penetration of passively transported drugs but may increase that of efflux system substrates like quinidine. Whether active transport systems like Pgp can be down regulated following icy LPS administration remains to be investigated.
DURATION OF GRAPEFRUIT JUICE EFFECT ON FEXOFENADINE INTERACTION. G.K. Dresser, MD~ R. B. Kim, MD, D. G. Bailey, PhD, Univ. of Western Ontario, London, ON & Vanderbilt Univ., Nashville, TN. Grapefruit juice (GFJ) reduces the oral bioavailability of fexofenadine (FEX), a non-metabolized substrate of certain OATP transporters. GFJ also interacts with CYP3A4 substrates even by juice given hours beforehand due to CYP3A4 inactivation. Prior GFJ ingestion was hypothesized to reduce FEX bioavailability. Twelve subjects received 300 ml GFJ or water (W) and FEX 120 mg in a randomized crossover study. GFJ was given at 0, 2, 4 or 10 hours prior to FEX. Results are shown (mean_+SE; *p
