Brain Disposition and Catalepsy After Intranasal Delivery of Loxapine: Role of Metabolism in PK/PD of Intranasal CNS Drugs
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To elucidate the role of metabolism in the pharmacokinetics and pharmacodynamics of intranasal loxapine in conscious animals.
At pre-determined time points after intranasal or oral loxapine administration, levels of loxapine, loxapine metabolites, and neurotransmitters in rat brain were quantified after catalepsy assessments (block test and paw test). Cataleptogenicity of loxapine was also compared with its metabolites.
Intranasally administered loxapine was efficiently absorbed into systemic circulation followed by entering brain, with tmax ≤15 min in all brain regions. Oral route delivered minimal amounts of loxapine to plasma and brain. Brain AUC0–240min values of 7-hydroxy-loxapine were similar after intranasal and oral administration. Intranasal loxapine tended to induce less catalepsy than oral loxapine, although statistical significance was not reached. The catalepsy score was positively and significantly correlated with the striatal concentration of 7-hydroxy-loxapine, but not with loxapine. 7-hydroxy-loxapine was more cataleptogenic than loxapine, while the presence of loxapine tended to reduce rather than intensify 7-hydroxy-loxapine-induced catalepsy. The increases in striatal dopamine turnover were comparable after intranasal and oral loxapine administration.
The metabolite 7-hydroxy-loxapine, but not loxapine, was the main contributor to the catalepsy observed after intranasal and oral loxapine treatment. Intranasal route could effectively deliver loxapine to brain.
KEY WORDSantipsychotics catalepsy central nervous system intranasal administration metabolism
area under the curve
central nervous system
time to maximum concentration
ACKNOWLEDGMENTS AND DISCLOSURES
CUHK Direct Grant 4450272 and General Research Fund CUHK 480809.
- 1.Wong YC, Zuo Z. Intranasal delivery–modification of drug metabolism and brain disposition. Pharm Res. 2010;27(7):1208–23.Google Scholar
- 4.Wong YC, Wo SK, Zuo Z. Investigation of the disposition of loxapine, amoxapine and their hydroxylated metabolites in different brain regions, CSF and plasma of rat by LC–MS/MS. J Pharm Biomed Anal. 2012;58(1):83–93.Google Scholar
- 22.Stille G, Lauener H. Pharmacology of catatonigenic substances. 1. Correlation between neuroleptic catalepsy and the homovanillic acid level in rat corpus striatum. Arzneimittelforschung. 1971;21(2):252–5.Google Scholar
- 23.Tareke E, Bowyer JF, Doerge DR. Quantification of rat brain neurotransmitters and metabolites using liquid chromatography/electrospray tandem mass spectrometry and comparison with liquid chromatography/electrochemical detection. Rapid Commun Mass Spectrom. 2007;21(23):3898–904.PubMedCrossRefGoogle Scholar
- 24.Diop L, Gottberg E, Briere R, Grondin L, Reader TA. Distribution of dopamine D1 receptors in rat cortical areas, neostriatum, olfactory bulb and hippocampus in relation to endogenous dopamine contents. Synapse. 1988;2(4):395–405.Google Scholar
- 26.Narige T, Mizumura M, Okuizumi N, Matsumoto K, Furukawa Y, Hondo T. Study of the absorption, distribution, metabolism, and excretion of amoxapine in rats. Yakuri to Chiryo. 1981;9(5):1885–92.Google Scholar
- 28.Tuk B, Van Oostenbruggen MF, Herben VMM, Mandema JW, Danhof M. Characterization of the pharmacodynamic interaction between parent drug and active metabolite in vivo: midazolam and alpha-OH-midazolam. J Pharmacol Exp Ther. 1999;289(2):1067–74.Google Scholar
- 31.Burki HR, Fischer R, Hunziker F. Dibenzo-epines: effect of the basic side-chain on neuroleptic activity. Eur J Med Chem. 1978;13(5):479–85.Google Scholar
- 38.Sztrymf B, Chevrel G, Bertrand F, Margetis D, Hurel D, Ricard J, et al. Beneficial effects of loxapine on agitation and breathing patterns during weaning from mechanical ventilation. Crit Care. 2010;14(3).Google Scholar
- 42.Hale RL, Munzar P, Rabinowitz JD, inventors. Alexza Molecular Delivery Corporation, USA, assignee. Method for treating pain with loxapine and amoxapine. Patent Application Country: Application: US; Patent Country: US; Priority Application Country: US patent 2004102434. 2004 0527; Patent Application Date: 20031120.; Priority Application Date: 20021126.Google Scholar
- 43.Kimishima K, Sakamoto T, Yamasaki M, Tanabe K, Amano Y. Central nervous actions of new neuroleptics, dibenzoazepine derivatives. Yonago Igaku Zasshi. 1969;20(6):525–36.Google Scholar