In vivo pharmacological profile of 9‐hydroxyrisperidone, the major metabolite of the novel antipsychotic risperidone

Abstract

Abstract9‐Hydroxyrisperidone (9OH‐risperidone) is the major metabolite of the new antipsychotic risperidone. 9OH‐risperidone was compared with risperidone in a series of pharmacological tests in rats; ritanserin and haloperidol were included as reference compounds in tests for 5HT2 and D2 antagonism, respectively. 9OH‐risperidone closely resembled risperidone and showed similar effects at closely related doses (respective subcutaneous [sc] ED50s in mg/kg in parentheses): 5HT2 antagonism: reversal of tryptamine cyanosis (0.00059/0.0011), inhibition and blockade of tryptamine seizures (0.032/0.014 and 0.11/0.056), inhibition of tryptamine tremors (0.34/0.049), inhibition and blockade of mescaline head twitches (0.056/0.037 and 0.098/0.049); D2 antagonism: inhibition and blockade of apomorphine behavior (0.34/0.22 and 4.1/1.2), inhibition and blockade of amphetamine agitation (0.15/0.056 and 0.51/0.59) and oxygen consumption (0.049/0.016 and 0.17/0.64), behavioral disinhibition (0.069/0.31) and depression (4.6/4.7) in amphetaminized rats; histamine H1 antagonism: protection from compound 48/80 lethality (0.018/0.014); α1‐adrenoceptor antagonism: protection from norepinephrine lethality (0.17/0.074); α2‐adrenoceptor antagonism: reversal of clonidine's antidiarrheal effect (0.29/0.67), reversal of xylazine loss of righting (16/2.4); and behavioral effects: slight and pronounced catalepsy (2.0/0.59 and 3.6/3.0), slight and pronounced palpebral ptosis (0.30/0.19 and 2.0/0.89), muscular hypotonia (4.7/3.6), hypothermia (4.1/2.0), inhibition of acetic acid writhing (1.2/0.34), and depression of motor activity (0.13/0.062 for vertical, 0.49/0.18 for horizontal, and 5.0/2.8 for total movements). Up to 10 mg/kg, both compounds were devoid of anti‐muscarinic and anti‐nicotinic activity, failed to affect the lethal effects of KCN, nitrogen, BaCl2 and ouabain, and did not block castor oil diarrhea. The acute oral LD50 values of the compounds were comparable. Both 9OH‐risperidone and risperidone differed markedly from haloperidol as indicated by: (1) predominant central 5HT2 antagonism (comparable to that of ritanserin); (2) high doses of catalepsy; (3) gradual depression of motor activity; (4) pronounced behavioral disinhibitory effects in amphetaminized rats; (5) inhibition of amphetamineinduced oxygen consumption preceding inhibition of amphetamine agitation. As metabolic conversion of risperidone to 9OH‐risperidone does apparently not result in any marked change in activity profile, its major consequence seems to be a prolongation of duration of action. © 1994 Wiley‐Liss, Inc.