Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate.
To evaluate the pharmacokinetic interaction between risperidone and the mood-stabilizing agents carbamazepine and valproic acid, steady state plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-risperidone) were compared in patients treated with risperidone alone (controls, n = 23) and in patients comedicated with carbamazepine (n = 11) or sodium valproate (n = 10). The three groups were matched for sex, age, body weight, and antipsychotic dosage. Plasma concentrations of risperidone and 9-OH-risperidone did not differ between valproate-comedicated patients and controls. By contrast, the concentrations of both compounds were lower in patients taking carbamazepine, although the difference reached statistical significance only for the metabolite (p < 0.001). The sum of the concentrations of risperidone and 9-OH-risperidone in patients receiving carbamazepine (median 44 nmol/L) was also significantly lower than in patients receiving valproate (168 nmol/L) and in controls (150 nmol/L). In five patients assessed with and without carbamazepine comedication, dose-normalized plasma risperidone and 9-OH-risperidone concentrations were significantly lower when the patients received combination therapy than when they received risperidone alone. In three patients assessed with and without valproate, no major changes in the levels of risperidone and its metabolite were observed. These findings demonstrate that carbamazepine markedly decreases the plasma concentrations of risperidone and its active 9-OH-metabolite, probably by inducing CYP3A4-mediated metabolism. This interaction is likely to be clinically significant. Conversely, valproic acid does not cause any major change in plasma antipsychotic levels.
Spina
E
E
Institute of Pharmacology, University of Messina, Italy.
Avenoso
A
A
Facciolà
G
G
Salemi
M
M
Scordo
M G
MG
Giacobello
T
T
Madia
A G
AG
Perucca
E
E
D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood*; D002220:Carbamazepine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000097:blood*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000502:physiology; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000097:blood*; D018967:Risperidone / Q000097:blood*; D014635:Valproic Acid / Q000494:pharmacology*
D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D002220:Carbamazepine; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D018967:Risperidone; D000068882:Paliperidone Palmitate