To study the multiple dose clinical pharmacokinetics of risperidone and its main active metabolite, 9-hydroxyrisperidone, in Chinese female patients with schizophrenia.
The subjects were 23 Chinese female inpatients aged 18–65 years who met the CCMD-III (third revision of the Chinese Criteria of Mental Disorders) criteria for schizophrenia. Subjects were tested after 17 d of treatment with 2 mg risperidone twice daily. Plasma concentrations of risperidone and 9-hydroxy-risperidone were assayed by using validated high performance liquid chromatography-mass spectrometry (HPLC-MS) methods.
Risperidone was rapidly absorbed (Tmax was 1.6 h) and its T1/2 in plasma was short (3.2 h). 9-hydroxy-risperidone was quickly metabolized from the parent drug with a mean Tmax of 2.5 h. It had a long half-life of 24.7 h. The Cssav of risperidone and 9-hydroxyrisperidone were 36.9±33.1 and 110.6±30.5 μg·h·L−1, respectively, and the AUCss0–12 were 443.2±397.4 and 1327.2±402.3 μg·h·L−1, respectively. CL/F and V/F of risperidone were 8.7±6.2 L/h and 34.1±24.3 L, respectively. Interindividual variations for pharmacokinetic parameters were quite large for risperidone. All 23 subjects experienced high prolactin levels when treated with risperidone. However there was no correlation between prolactin level and the concentration of risperidone, 9-hydroxy-risperidone, or the active moiety.
Risperidone showed large interindividual variations in pharmacokinetics. Administration of risperidone resulted in high serum prolactin levels. The results indicate that systemic exposure to risperidone and 9-hydroxy-risperidone in female Chinese schizophrenic patients is higher relative to published data for white Caucasian patients. Larger studies regarding the PK/PD relationship may be required to develop a reasonable clinical dosage regimen for Chinese female patients.
Janssen PA, Niemegeers CJ, Awouters F, Schellekens KH, Megens AA, Meert TF . Pharmacology of risperidone (R64766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 1988; 244: 685–93.
Marder SR, Davis DM, Chouinard D . The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997; 58: 538–46.
Mesotten F, Suy E, Pietquin M, Burton P, Heylen S, Gelders Y . Therapeutic effect and safety of increasing doses of risperidone (R64766) in psychotic patients. Psychopharmacology 1989; 99: 445–9.
Huang F, Lasseter KC, Janssens L . Pharmacokinetics and safety assessments of Galantamine and Risperidone after the two drugs are administered alone and together. J Clin Pharmacol 2002; 42: 1341–51.
He H, Richardson JS . A pharmacological, pharmacokinetic and clinical overview of risperidone, a new antipsychotic that blocks serotonin 5–HT2 and dopamine D2 receptors. Int Clin Psycho-pharmacol 1995; 10: 19–30.
Mannens G, Huang ML, Meuldermans W . Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos 1993; 21: 1134–41.
Koymans L, Vermeulen NP, van Acker SA . A predictive model for substrates of cytochrome P450-debrisoquine (2D6). Chem Res Toxicol 1992; 5: 211–9.
Beijsterveldt V, Geerts JFR, Lseysen JE . The regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacol 1993; 15: 371–9.
Fang J, Bourin M, Baker GB . Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol 1999; 359: 147–51.
Yasui-Furukori N, Hidestrand M, Spina E . Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos 2001; 29: 1263–8.
Nyberg S, Dahl ML, Halldin C . A PET study of D2 and 5–HT2 receptor occupancy induced by risperidone in poor metabolizers of debrisoquin and risperidone. Psychopharmacology (Berl) 1995; 119: 345–8.
Huang ML, van Peer A, Woestenborghs R, De Coster R, Heykants J, Jansen AA, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54: 257–68.
Heykants J, Huang ML, Mannens G, Meuldermans W, Snoeck E, Van Beijsterveldt L, et al. The pharmacokinetics of risperidone in humans: a summary. J Clin Psychiatry 1994; 55 Suppl: 13–7.
Ereshefsky L, Lacombe S . Pharmacological profile of risperidone. Can J Psychiatry 1993; 38 Suppl 3: S80–8.
Wei X . To review the data of epidemiological survey of schizophrenia. Chin Gen Practice 2003; 8: 669–70.
Shen YC . Discussion of the data of prevalence survey of all kinds of mental diseases. Chin J Neurol Psychiatry 1986; 19: 80–2.
Shen YC, Chen CH . Analysis of the data and methodology of epidemiological survey of schizophrenia in 12 Chinese regions. Chin J Neurol Psychiatry 1986; 19: 65–9.
Xi W . An epidemiological survey of schizophrenia inpatients. Chin J Behav Med Sci 1999; 34: 50–1.
Wang C . A prevalence survey of schizophrenia in Yichun city of Jiang Xi Province. Sichuan Psychiatry Sci 2002; 15: 178–9.
Wang SJ . An epidemiological survey on schizophrenia in Fuyang, Anhui (1984-1994). J Chin Psychol Med 2002; 12: 3–4.
Cui LJ, Tian GQ, Zhao SM . Serum levels of prolactin and growth hormone and effect of pharmacotherapy on schizophrenia: a comparative study of risperidone and chlorpromazine. Chin Mental Health J 2000; 13: 368–70.
Gao ZS, Wu SY . Sex differences of social psychic factors effecting on community patients with schizophrenia. J Clin Psychosomatic Diseases 1999; 3: 1–3.
Liu GQ, Xiang MZ, Yang MS . Study of the sex differences of patients with schizophrenia in the community of countryside. J North Sichuan Med College 1998; 13: 70–1.
Zhou Z, Li X, Li K, Li H . Simultaneous determination of clozapine, olanzapine, risperidone and quetiapine in plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. J Chromat B 2004; 802: 257–62.
Li KY, Cheng ZN, Li X, Bai XL, Zhang BK, Wang F, et al. Simultaneous determination of quetiapine and three metabolites in human plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. Acta Pharmacol Sin 2004; 25: 110–4.
Balant-Gorgia AE, Androniki E . Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: Reappraisal of interindividual variability factors. Ther Drug Monit 1999; 21: 105–15.
Spina E, Avenoso A, Facciola G . Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psychopharmacology (Berl) 2001; 153: 238–43.
Bondolfi G, Eap CB, Bertschy G . The effect of fluoxetine on the pharmacokinetics and safety of risperidone in psychiatric patients. Pharmacopsychiatry 2002; 35: 50–6.
Reyes JF, Preskorn SH, Khan A . Concurrent administration of donepezil HCl and risperidone in patients with schizophrenia: assessment of pharmacokinetic changes and safety following multiple oral doses. Br J Clin Pharmacol 2004; 58 Suppl 1: 50–7.
Castberg I, Spigset O . Serum concentrations of risperidone and 9-hydroxyrisperidone after administration of the long-acting injectable form of risperidone: evidence from a routine therapeutic drug monitoring service. Ther Drug Monit 2005; 27: 103–6.
Transon C, Lecoeur S, Leemann T, Beaune P, Dayer P . Interindividual variability in catalytic activity and immunoreactivity of three major human liver cytochrome P450 isozymes. Eur J Clin Pharmacol 1996; 51: 79–85.
Shu Y, Cheng ZN, Liu ZQ, Wang LS, Zhu B, Huang SL, et al. Interindividual variations in levels and activities of cytochrome P-450 in liver microsomes of Chinese subjects. Acta Pharmacol Sin 2001; 22: 283–8.
Berecz R, Dorado P, De La Rubia A, Caceres MC, Degrell I, Lerena A . The role of cytochrome P450 enzymes in the metabolism of risperidone and its clinical relevance for drug interactions. Curr Drug Targets 2004; 5: 573–9.
Han XM, Zhou HH . Polymorphism of CYP450 and cancer susceptibility. Acta Pharmacol Sin 2000; 21: 673–9.
Chen SQ, Wedlund PJ . Correlation between cytochrome P-450 CYP2D6 (CYP2D6) genotype and phenotype. Acta Pharmacol Sin 1999; 20: 585–8.
Cai WM, Chen B, Liu YX, Chu X . Dextromethorphan metabolic phenotyping in a Chinese population. Acta Pharmacol Sin 1997; 18: 441–4.
Boulton DW, DeVane CL, Liston HL . In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci 2002; 71: 163–9.
Thiebaut F, Tsuruo T, Hamada H . Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987; 84: 7735–8.
Yang HT, Wang GJ . Transport and uptake characteristics of a new derivative of berberine (CPU-86017) by human intestinal epithelial cell line: Caco-2. Acta Pharmacol Sin 2003; 24: 1185–91.
Rao VV, Dahlheimer JL, Bardgett ME . Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood- cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci USA 1999; 96: 3900–5.
He L, Liu GQ . Interaction of multidrug resistance reversal agents with P-glycoprotein ATPase activity on blood-brain barrier. Acta Pharmacol Sin 2002; 23: 423–9.
Ayrton A, Morgan P . Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica 2001; 31: 469–97.
Deberdt WG, Dysken MW, Rappaport SA . Comparison of olanzapine and risperidone in the treatment of psychosis and associated behavioral disturbances in patients with dementia. Am J Geriatr Psychiatry 2005; 13: 722–30.
Knegtering R, Baselmans P, Castelein S . Predominant role of the 9-hydroxy metabolite of risperidone in elevating blood prolactin levels. Am J Psychiatry 2005; 162: 1010–2.
Kakihara S, Yoshimura R, Shinkai K, Matsumoto C, Goto M, Kaji K, et al. Prediction of response to risperidone treatment with respect to plasma concentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6. Int Clin Psychopharmacol 2005; 20: 71–8.
About this article
Cite this article
Zhou, Z., Li, X., Peng, H. et al. Multiple dose pharmacokinetics of risperidone and 9-hydroxyrisperidone in Chinese female patients with schizophrenia. Acta Pharmacol Sin 27, 381–386 (2006) doi:10.1111/j.1745-7254.2006.00256.x
Improving prediction of torsadogenic risk in the CiPA in silico model by appropriately accounting for clinical exposure
Journal of Pharmacological and Toxicological Methods (2019)
Impact of Chronic Risperidone Use on Behavior and Survival of 3xTg-AD Mice Model of Alzheimer’s Disease and Mice With Normal Aging
Frontiers in Pharmacology (2019)
Physiologically Based Pharmacokinetic Modelling to Describe the Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone According to Cytochrome P450 2D6 Phenotypes
Clinical Pharmacokinetics (2019)
Optimization of maintenance therapy of Risperidone with CYP2D6 genetic polymorphisms through an extended translational framework-based prediction of target occupancies/clinical outcomes
Pharmacological Research (2018)
Prolactin levels: sex differences in the effects of risperidone, 9-hydroxyrisperidone levels, CYP2D6 and ABCB1 variants