Brain disposition and catalepsy after intranasal delivery of loxapine: role of metabolism in PK/PD of intranasal CNS drugs.

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

methodsAt 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.

resultsIntranasally 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.

conclusionsThe 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.