title: Conjugation with L-Glutamate for in vivo brain drug delivery.
abstract: In vitro studies have shown that conjugation of a model compound [p-di(hydroxyethyl)-amino-D-phenylalanine (D-MOD)] with L-Glu can improve D-MOD permeation through the bovine brain microvessel endothelial cell monolayers (Sakaeda et al., 2000). The transport of this D-MOD-L-Glu conjugate is facilitated by the L-Glu transport system. In this paper, we evaluate the in vivo brain delivery of model compounds (i.e. D-MOD, p-nitro-D-phenylalanine (p-nitro-D-Phe), 5,7-dichlorokynurenic acid (DCKA) and D-kyotorphin) and their L-Glu conjugates. DCKA was also conjugated with L-Asp and L-Gln amino acids. The analgesic activities of D-kyotorphin and its L-Glu conjugate were also evaluated. The results showed that the brain-to-plasma concentration ratio of D-MOD-L-Glu was higher than the D-MOD alone; however, the plasma concentration of both compounds were the same. The plasma concentration of p-nitro-D-Phe-L-Glu conjugate was higher than the parent p-nitro-D-Phe; however, the brain-to-plasma concentration ratio of p-nitro-D-Phe was higher than its conjugate. On the other hand, both DCKA and DCKA conjugates have a low brain-to-plasma concentration ratio due to their inability to cross the blood-brain barrier (BBB). The L-Asp and L-Glu conjugates of DCKA have elevated plasma concentrations relative to DCKA; however, the DCKA-L-Gln conjugate has the same plasma concentration as DCKA. For D-kyotorphin, both the parent and the L-Glu conjugate showed similar analgesic activity. In conclusion, conjugation of a non-permeable drug with L-Glu may improve the drug's brain delivery; however, this improvement may depend on the physicochemical and receptor binding properties of the conjugate.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co., Ltd., 5-12-4, Sagisu Fukushima-ku, Osaka, 553-0002, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Y
authors.initials: Y
authors.lastname: Tada
authors.forename: T
authors.initials: T
authors.lastname: Sugawara
authors.forename: T
authors.initials: T
authors.lastname: Ryu
authors.forename: F
authors.initials: F
authors.lastname: Hirose
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: K
authors.initials: K
authors.lastname: Hirano
authors.forename: L
authors.initials: L
authors.lastname: Kupczyk-Subotkowska
authors.forename: T J
authors.initials: TJ
authors.lastname: Siahaan
authors.forename: K L
authors.initials: KL
authors.lastname: Audus
authors.forename: V J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002199:Capillary Permeability; D016503:Drug Delivery Systems; D004341:Drug Evaluation; D004723:Endorphins / Q000493:pharmacokinetics; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008297:Male; D008558:Melphalan / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004723:Endorphins; D011355:Prodrugs; C019448:kyotorphin; D018698:Glutamic Acid; D010649:Phenylalanine; D007736:Kynurenic Acid; D008558:Melphalan; C066192:5,7-dichlorokynurenic acid