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

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ABSTRACT

Purpose

To elucidate the role of metabolism in the pharmacokinetics and pharmacodynamics of intranasal loxapine in conscious animals.

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

3-MT:

3-methoxytyramine

5-HIAA:

5-hydroxyindole-3-acetic acid

5-HT:

Serotonin

7-OH-amoxapine:

7-hydroxy-amoxapine

7-OH-loxapine:

7-hydroxy-loxapine

8-OH-amoxapine:

8-hydroxy-amoxapine

8-OH-loxapine:

8-hydroxy-loxapine

AUC:

area under the curve

Cmax :

maximum concentration

CNS:

central nervous system

CYP:

cytochrome P450

DA:

dopamine

DOPAC:

3,4-dihydroxyphenylacetic acid

HVA:

homovanillic acid

IM:

intramuscular

IV:

intravenous

PD:

pharmacodynamics

PK:

pharmacokinetics

t1/2 :

half life

tmax :

time to maximum concentration

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ACKNOWLEDGMENTS AND DISCLOSURES

CUHK Direct Grant 4450272 and General Research Fund CUHK 480809.

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  1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Room 801C Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, New Territories, Hong Kong

    Yin Cheong Wong & Zhong Zuo

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  1. Yin Cheong Wong
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  2. Zhong Zuo
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Correspondence to Zhong Zuo.

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Wong, Y.C., Zuo, Z. Brain Disposition and Catalepsy After Intranasal Delivery of Loxapine: Role of Metabolism in PK/PD of Intranasal CNS Drugs. Pharm Res 30, 2368–2384 (2013). https://doi.org/10.1007/s11095-013-1080-x

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