Microsoft word - asian2004-4_303-306, zhang zp_.doc

Asian Journal of Drug Metabolism and Pharmacokinetics
Copyright by Hong Kong Medical Publisher
ISSN 1608-2281 2004; 4(4): 303-306

Biochemical mechanism of comparison studies of clozapine and
quetiapine by metabonomic method in rats

Zong-Peng Zhang, Ya Su, Nan Yue, Yi-Gui Zhao
Tianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China Abstract
Aim Using metabonomic method to study the biochemical mechanism of antipsycholic agents through
determining the metabolism of dopaminergic neurotransmitters in brain tissues after administration of
clozapine and quetiapine in rats. Methods The determination of serotonin (5-HT), noeradrenaline (NA),
5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid
(HVA) in diencephalons and striata by HPLC with electrochemical detector following oral administration
of clozapine and quetiapine in rats. Results At doses of clozapine 40 mg·kg-1 and quetiapine 20 and 40
mg·kg-1, they were able to raise the concentrations of DOPAC and HVA in diencephalons and striata.
Conclusion The study result suggested that clozapine and quetiapine stimulated dopamine metabolism. It
could be relative with the antipsychotic pharmacological activity.

Key words
Biochemical mechanism; clozapine; quetiapine; metabonomics;antipsychotics; neurotransmitter Introduction
marketed name by AstraZeneca),which is a novel dibenzothiazepine antipsychotic developed by Clozapine is the first of a new generation of Zeneca , is an atypical antipsychotic with many antipsychotic drugs which constitutes a major similarities to clozapine. Both placebo-controlled and advance in the treatment of schizophrenia. Numerous comparative studies in patients with schizophrenia theories have been proposed to explain the have demonstrated that quetiapine has long-term advantages of clozapine over typical neuroleptics. efficacy in both positive and negative domains, as Most of these focus on its effects on dopaminergic well as beneficial effects on affective and cognitive and serotonergic neurotransmission. This article symptoms. Comparative clinical studies confirm that reviews the effects of clozapine and related quetiapine is at least as effective as the standard antipsychotics, chlorpromazine and haloperidol and response rates with quetiapine are similar to those 4, and serotonin (5-HT) 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, as well as its ability to reported with other atypical antipychotics.[3,4] mo d u la te DA and 5 -HT r e lea s e. [ 1] S ev er a l Quetiapine is well tolerated and clinically effective in post-mortem studies have identified increases of the treatment of schizophrenia. The initial hope of 5-HT1A receptor density in frontal cortical areas in investigators was that quetiapine would have schizophrenic patients, and one has found increases antipsychotic potential and that it might share some in the cerebellar vermis. Clozapine has moderate of the properties of clozapine without its toxicity to affinity at the 5-HT1A receptor, and this may be of therapeutic importance.[2] Quetiapine (Seroquel, In this present study, using metabonomic method studied the biochemical mechanism of Correspondence to Prof Zong-Peng Zhang, 308 An-Shan West antipsycholic agents through determining the Road, Research Centre for New Drug Evaluation, Tianjin Institute metabolism of dopaminergic neurotransmitters in of Pharmaceutical Research, Tianjin, 300193, China Tel: +-86 brain tissues after administration of clozapine and quetiapine in rats for comparison of the dopamine 5-HT), and the metabolites, noeradrenaline (NA), 3,4-dihydroxyphenylacetic acid (DOPAC), and Materials and methods
homovanillic acid (HVA) in biosamples by Waters Test animals Wister male rats with body
weight 280-350 g were produced by The animal The condition for determination of 5-HT,
department of Tianjin Institute of Pharmaceutical 5-HIAA, DOPAC and HVA The determination of
Research, Tianjin, China. The rank of experiment 5-HT, 5-HIAA, DOPAC, and HVA in biosamples was establishment was 2 levels. All animals were housed performed by Waters 6000 HPLC with BASLC-4B electrochemical detector. The analytical columns was C18, 5 µm, 150 mm x 4.6 mm I.D. The columns were Test drugs Clozapine was produced by
maintained at 30°C using a temperature controller. Dong-Teng Pharmaceuticas company. Batch Number: The mobile phase consisted of a mixture of 1000 mL 962004. Quetiapine was produced by the Chemical buffer (50 mmol·L-1 sodium citrate, 25 mmol·L-1 Department of Tianjin Institute of Pharmaceutical monobasic sodium phosphate, 10 mmol·L-1 diethylamine hydrochloride, 2.2 mmol·L-1 sodium Reagents Dopamine (DA) , noeradrenaline
octylsulfonate and 0.03 mmol·L-1 disodium EDTA, (Norepinephrine, NA), dihydroxyphenylacetic acid pH 3.2, adjusted with 85% phosphoric acid), 30 mL (DOPAC),and homovanillic acid (HVA),were acetonitrile, 15 mL dimethyl-acetamide, and was filtered through a 0.20 µm filter. The flow rate was Appearance Waters 6000 HPLC with
0.8 mL·min-1. Detection was at a glassy carbon Test method Thirty Wister rats were divided
maintained at a potential of +700 mV vs. Ag/AgCl. into three groups at random (10 eachgroup) and were Using peak high of standard calculates the treated by single oral dose of experimental control concentrations of neurotransmitters and their reagent, clozapine (40mg·kg-1) and seroquel metabolites. (40mg·kg-1) respectively. All rats were decollated one Data Analysis
hour after drug administration, diencephalons and Concentrations of all analytes are expressed as striata were separated out on ice, weighed, and the mean ± SD in the dialysates. For statistical prepared for homogenates at 15000 r·min-1 for 20 analysis, the within group concentration of the seconds after adding 2mL 0.2mmol·L-1 HClO4 cold analytes collected before administration of melatonin solution. The homogenates were then centrifuged at were compared with those collected after 10000 r·min-1 for 10 minutes in high-speed administration using Student’s t-test. For all statistical analyses, a p value of 0.05 or less was considered According to references[6,7] and the established method in our laboratory to determine concentrations of Dopamine(DA), 5-hydroxytryptamine (serotonin, Table 1 Effects of Clozapine and Quetiapine on metabolism of dopamine and noeradrenaline in brain of rats Concentration (μg/g brain tissue)mean±SD 10 1.33±0.37 4.32±0.71 0.93±0.33 1.61±0.39 1.82±0.43** 5.12±1.53 1.61±0.43** 1.52±0.42 2.10±0.51** 5.06±1.26 1.50±0.22** 1.52±0.27 concentrations of DOPAC and HVA in diencephalons and striata. The results were listed in Table 1. It At doses of clozapine 40mg·kg-1 and quetiapine showed that in the two groups, clozapine 40mg·kg-1 20 and 40mg·kg-1, they were able to raise the and quetiapine 40mg·kg-1 the concentrations of DOPAC and HVA were markedly high than these of receptors.[6] Results of this study show that clozapine in control group (P<0.01), and the concentrations of and quetiapine can improve the metabolism of DA in DA and NA were no different between clozapine or diencephalons and striata, and this biochemical quetiapine group and control group. The study result mechanism may be related to their pharmacological suggested that clozapine and quetiapine stimulated According to the data in Table 1, analyzing the demonstrated enormous potential in furthering the effect of the two on drugs metabolic pathway (Fig 1) understanding of, for example, disease processes, suggests that DA is formed middle metabolite toxicological mechanisms, and biomarker discovery. DOPAC (dihyrdoxy phenyl acetic acid) by MAO The biochemical mode-of-action for herbicides and (monoamine oxidase), and last formed HVA by other bioactive compounds can be rapidly and COMT (catechel-O-methyl transferase). The similar simultaneously classified by automated pattern effect of two drugs on DA metabolic pathway is recognition of the metabonome. Metabonomics can considered that they possess increasing dopaminergic be applied at any stage in drug discovery and development processes, when used in one or more of the following settings: predictive biomarkers for drug-related effects in animal models; understanding DA ────→ DOPAC───→ HVA
of the biochemical mechanisms of action to target-organ or to target-organ pathologies in animal to man; developing biomarkers for toxicities in non-clinical development; and predictive biomarkers Discussion
for drug-related effects in man during Phase II and Phase III clinical trails.[9-13 Metabonomics can be In the central nervous system, dopaminergic directly understood as the physiological and neurotransmission is mediated through two main biochemical situation by its “metabonome profile” as types of postsynaptic receptors termed D1 and D2. a whole. In this pare, we applied metabonomic The D1 receptor is linked to stimulation of adenylate method to discover the biochemical mechanism of cyclase; D2 receptor either inhibit adenylate cyclase antipsycholic agents through determining the change or are linked to phospholipase C, postassium channels or calcium mobilization. The clinical potency of antipsychotic agents correlateds best with the affinity for D2 receptor. Compared with other References
antpsychotics, clozapine has weak dopaminergic Meltzer HY. Role of serotonin in the action of atypical potency. This characteristic may be correlated with antipsychotic drugs. Clin Neurosci. 1995;3(2):64-75. Bantick RA, Montgomery AJ, Bench CJ, Choudhry T, Malek that the antagonizing action of clozapine on 5-TH and N, McKenna PJ, Quested DJ, Deakin JF, Grasby PM. A D2 receptors is weak. The specific mechanism by positron emission tomography study of the 5-HT1A receptor which antupsychotic drugs wxwrt their therapeutic in Schizophrenia and during clozapine treatment. J effects is not completely understood; however, Psychopharmacol. 2004;18(3):346-54. research has shown that antipsychotic drugs affecting Kasper S, Muller-Spahn F. Review of quetiapine and its dopaminergic receptor; and these drugs have variying clinical applications in schizophrenia. Expert Opin Pharmacother. 2000; 1(4):783-801. Migler BM, Warawa EJ. Seroguel :behavioral effects in Quetiapine is an atypical antipsychotic with conventional and novel tests for atypical antipsychotic drug. many similarities to clozapine. The published studies Psychopharmacology 1993; 112:299-307. showed that positive symptoms of schizophrenia are Green B. Focus on quetiapine. Curr Med Res Opin. caused by hyperfunction of dopamine in limbic system of diencephalons, while negative symptoms Saller CF, Salama AI. Seroquel :biochemical profile of a potential atypical antipsychotic drug. Psychopharmacology are related to the decrease of activity of dopamine in prefrontal lobe and mechanism of 5-HT. Clozapine 7 Qu ZW, Zhang JT Determination of dopaminergic and quetiapine have strong affinity to 5-HT1A neurotransmitters by HPLC-ECD. Institute of Materia receptors and relatively weak affinity to D2 Medica, Chinese Academy of Medical Sciences 1995; 48-50. American Medical Association. Drug Evaluations Annual Journal of Drug Metabolism and Pharmacokinetics 2004; 1992. Chicago: American Medical Association. 1992; 246. Lindon JC, Holmes E, Nicholson JK. Metabonomics and its Liu CX. Application of metabonomics in drug discovery and role in drug development and disease diagnosis. Expert Rev development. Post-gene-time: Drug Diascovery (Ed He FC) Beijing: Military Medical Science Press 2004, 17-20. Lindon JC, Holmes E, Nicholson JK. So what's the deal with Liu CX. Significance of metabonomics in modern research of metabonomics? Anal Chem 2003; 75(17):384A-391A. Chinese traditional and herbal drugs. Chinese Traditional and 11 Liu CX, Li C, Lin DH , Song NN. Significance of metabonomics in drug discovery and development Asian



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