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.
Pharm Res. 2013 Sep;30(9):2368-84. doi: 10.1007/s11095-013-1080-x. Epub 2013 Jun 7.
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.
阐明代谢在清醒动物经鼻给予洛沙平的药代动力学和药效学中的作用。
在经鼻或口服洛沙平给药后预定的时间点，在进行僵住评估（阻滞试验和爪试验）后定量测定大鼠脑内洛沙平、洛沙平代谢物和神经递质的水平。还比较了洛沙平与其代谢物的致僵作用。
经鼻给予的洛沙平被有效地吸收到体循环中，然后进入大脑，所有脑区的 tmax≤15 分钟。口服途径向血浆和大脑输送的洛沙平最少。经鼻和口服给药后，7-羟基洛沙平的脑 AUC0-240min 值相似。经鼻洛沙平引起的僵住作用倾向于比口服洛沙平少，尽管未达到统计学意义。僵住评分与纹状体中 7-羟基洛沙平的浓度呈正相关且显著相关，但与洛沙平无关。7-羟基洛沙平比洛沙平更具致僵作用，而洛沙平的存在倾向于减轻而非加剧 7-羟基洛沙平引起的僵住作用。经鼻和口服洛沙平给药后，纹状体多巴胺周转率的增加相当。
代谢物 7-羟基洛沙平，而不是洛沙平，是经鼻和口服洛沙平治疗后观察到的僵住的主要原因。经鼻途径可有效将洛沙平递送到大脑。
