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Pharmacokinetic Comparison Between the Long-Term Anesthetized, Short-Term Anesthetized and Conscious Rat Models in Nasal Drug Delivery

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Abstract

Purpose

To investigate the pharmacokinetic differences between the common nasal delivery models.

Methods

In three different rat models [long-term anesthetized (with nasal surgery), short-term anesthetized (without nasal surgery) and conscious models], tacrine and loxapine were administered via nasal, intravenous and oral routes, and the plasma pharmacokinetics were compared among different models.

Results

Systemic exposures of both drugs and their metabolites were consistently higher in long-term anesthetized model after all routes of administration in comparison to that of conscious model. Nasal bioavailabilities in long-term anesthetized model (tacrine 83%, loxapine 97%) were much higher than that in conscious model (tacrine 10%, loxapine 46%). Further studies on tacrine and its metabolites demonstrated no significant difference in t1/2 between short-term anesthetized and conscious models after all routes of administration; however, long-term anesthetized model showed significantly longer t1/2. Regarding the pharmacokinetic parameters (Cmax, Tmax, AUC, bioavailability) of tacrine and its metabolites, short-term anesthetized model resembled closer to conscious model than long-term anesthetized model.

Conclusions

Plasma clearances of tacrine, loxapine, and their metabolites were much slower in the long-term anesthetized model of nasal delivery probably due to suppressed hepatic and renal clearances, while the short-term anesthetized model imposed less impact on tacrine pharmacokinetics and metabolism.

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Abbreviations

1-OH-THA:

1-hydroxytacrine

2-OH-THA:

2-hydroxytacrine

4-OH-THA:

4-hydroxytacrine

7-OH-AMOX:

7-hydroxyamoxapine

7-OH-LOX:

7-hydroxyloxapine

8-OH-AMOX:

8-hydroxyamoxapine

8-OH-LOX:

8-hydroxyloxapine

AMOX:

Amoxapine

AUC:

Area under the curve

CLtotal :

Total systemic clearance

Cmax :

Maximum concentration

CYP:

Cytochrome P450

GI:

Gastrointestinal

i.n.:

Intranasal

i.v.:

Intravenous

LOX:

Loxapine

p.o.:

Oral

PK:

Pharmacokinetics

t1/2 :

Elimination half life

THA:

Tacrine

Tmax :

Time to reach maximum concentration

Vd :

Volume of distribution

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Acknowledgments AND Disclosures

Yin Cheong Wong and Shuai Qian made equal contributions to this work. This work was funded by CUHK Direct Grant 4450272 and General Research Fund CUHK 480809. The authors are grateful to Ms. Sophia Yui Kau Fong for her valuable suggestions to the manuscript.

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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, Shuai Qian & Zhong Zuo

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Wong, Y.C., Qian, S. & Zuo, Z. Pharmacokinetic Comparison Between the Long-Term Anesthetized, Short-Term Anesthetized and Conscious Rat Models in Nasal Drug Delivery. Pharm Res 31, 2107–2123 (2014). https://doi.org/10.1007/s11095-014-1312-8

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