NDLI: Evaluation of Blood-Brain Barrier Passage of a Muscarine M1 Agonist and a Series of Analogous Tetrahydropyridines Measured by In Vivo Microdialysis

Content Provider	Springer Nature Link
Author	Sveigaard, Helle Hagen Dalgaard, Lars
Copyright Year	2000
Abstract	Purpose. To investigate the blood-brain barrier (BBB) passage of theM1 muscarine agonist Lu 25-109(5-(2-Ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-methylpyridine) and potential metabolites using in vivomicrodialysis. Methods. Anesthetized rats were administered an intravenous infusionof one of seven analogs with a Log D$_{7.4}$ ranging from 0.35 to −2.4.Microdialysis probes were implanted in the brain and the jugular vein.The integrity of the BBB was evaluated using2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA), a compound notexpected to penetrate the BBB. The data was corrected for in vitrorecovery. Results. Lu 25-109, Lu 24-165 (demethylated Lu 25-109) and Lu25-077 (N-demethylated Lu 25-109) entered the brain in a 1:1 ratio withthe blood. Although Lu 29-081 (hydroxylated Lu 25-109) presented asimilar Log D$_{7.4}$ to Lu 25-109 and Lu 24-164, it entered the brain witha lower brain:blood ratio of 0.5. Lu 32-181 (Lu 25-109 N-oxide), Lu35-026 (deethylated and oxidized Lu 25-109) and Lu 31-126(deethylated Lu 25-109) were not detected in the brain samples, indicating nopenetration. Infusion of Lu 25-109 resulted in a time perspective ofthe formation and distribution of the two metabolites Lu 25-077 andLu 32-181. Although the hydroxylated compound (Lu 29-081) had aLog D$_{7.4}$ of −0.6, within the range 0.35 to −0.83 of the compoundspenetrating the BBB, it showed a brain: blood ratio of 0.5. Lu 35-026showed an unusual infusion profile with a t$_{max}$ of 100–150 min and asubsequent decrease in blood concentration. Conclusions. Compounds with Log D$_{7.4}$ above −0.83 penetrated theBBB, whereas compounds below −1.5 did not. Knowledge of LogD$_{7.4}$ values is not sufficient to evaluate BBB passage because the valuedoes not predict the influence of active transport processes.
Starting Page	70
Ending Page	76
Page Count	7
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	17
Issue Number	1
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2000-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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