Pharmaceutical Research

, Volume 30, Issue 9, pp 2368–2384 | Cite as

Brain Disposition and Catalepsy After Intranasal Delivery of Loxapine: Role of Metabolism in PK/PD of Intranasal CNS Drugs

  • Yin Cheong Wong
  • Zhong Zuo
Research Paper



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.


antipsychotics catalepsy central nervous system intranasal administration metabolism 





5-hydroxyindole-3-acetic acid












area under the curve


maximum concentration


central nervous system


cytochrome P450




3,4-dihydroxyphenylacetic acid


homovanillic acid










half life


time to maximum concentration



CUHK Direct Grant 4450272 and General Research Fund CUHK 480809.

Supplementary material

11095_2013_1080_MOESM1_ESM.docx (379 kb)
ESM 1 (DOCX 379 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.School of Pharmacy, Faculty of MedicineThe Chinese University of Hong KongShatinHong Kong

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