Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism of risperidone (100 microM) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8, CYP2C9-arg144, CYP2C9-cys144, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol(-1) CYP min(-1), respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore, inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat.
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PMID:Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. 1004

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.
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PMID:Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. 1036 50

The introduction of the atypical antipsychotics clozapine, risperidone, olanzapine, quetiapine and sertindole for the treatment of schizophrenia has coincided with an increased awareness of the potential of drug-drug interactions, particularly involving the cytochrome P450 (CYP) enzymes. The current literature describing the pharmacokinetics of the metabolism of these agents, including their potential to influence the metabolism of other medications, is reviewed. Clozapine appears to be metabolized primarily by CYP1A2 and CYP3A4, with additional contributions by CYP2C19 and CYP2D6. In addition, clozapine may inhibit the activity of CYP2C9 and CYP2C19, and induce CYP1A, CYP2B and CYP3A. Risperidone is metabolized by CYP2D6, and possibly CYP3A4. In vitro data indicate that olanzapine is metabolized by CYP1A2 and CYP2D6. Quetiapine is metabolised by CYP3A4 and sertindole by CYP2D6. There is, however, a general paucity of in vivo data regarding the metabolism of the atypical antipsychotics, indicating a need for further research in this area.
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PMID:Drug metabolism and atypical antipsychotics. 1042 90

Risperidone, an atypical antipsychotic drug, is widely used in the treatment of psychoses associated with schizophrenia, Alzheimer's disease, and other psychiatric disorders. Polypharmacology is a necessary condition for the optimal treatment of many patients with comorbid psychiatric and medical illness. One concern raised by the widespread use of multiple concurrent pharmacotherapies is the potential for drug-drug interactions to adversely affect patient outcome. Accordingly, the biomedical literature was reviewed for reports of drug interactions involving risperidone, and the clinical significance of each report was evaluated. Additionally, the potential for risperidone to participate in drug interactions was evaluated by considering the drug's pharmacokinetic properties. Controlled studies and case reports indicate that risperidone has a low potential for metabolic drug interactions. Drugs that inhibit cytochrome P450 (CYP) 2D6 or induce or inhibit CYP3A4 may alter risperidone plasma concentrations, but the clinical significance of such interactions seems to be minimal. Adherence to a few guidelines for the design of dosage regimens should limit the effect of drug-drug interactions on patient status and contribute to optimal pharmacotherapy with risperidone.
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PMID:An evaluation of risperidone drug interactions. 1147 25

Antipsychotic drugs are used for the treatment of schizophrenia and other related psychotic disorders. The antipsychotics currently available include older or classical compounds and newer or atypical agents. Most antipsychotic drugs are highly lipophilic compounds and undergo extensive metabolism by cytochrome P450 (CYP) enzymes in order to be excreted. There is a wide interindividual variability in the biotransformation of antipsychotic drugs, resulting in pronounced differences in steady-state plasma concentrations and, possibly, in therapeutic and toxic effects, during treatment with fixed doses. Many classical and some newer antipsychotics are metabolized to a significant extent by the polymorphic CYP2D6, which shows large interindividual variation in activity. Other CYPs, especially CYP1A2 and CYP3A4, also contribute to the interindividual variability in the kinetics of antipsychotics and occurrence of drug interactions. No relationship between CYP2D6 genotype or activity and therapeutic effects of classical antipsychotic drugs has been found in the few studies performed. On the other hand, some investigations suggest that poor metabolizers (PMs) of CYP2D6 would be more prone to over-sedation and, possibly, Parkinsonism during treatment with classical antipsychotics, while other studies, mostly retrospective, have been negative or inconclusive. For the newer antipsychotics, such data are lacking. To date, CYP2D6 phenotyping and genotyping appear, therefore, to be clinically useful for dose predicting only in special cases and for a limited number of antipsychotics, while their usefulness in predicting clinical effects must be further explored.
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PMID:Cytochrome P450 polymorphisms and response to antipsychotic therapy. 1197 42

The effect of fluoxetine on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was evaluated in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized on risperidone (4-6 mg/day) received additional fluoxetine (20 mg/day) to treat concomitant depression. One patient dropped out after 1 week due to the occurrence of akathisia associated with markedly increased plasma risperidone concentrations. In the other subjects, mean plasma concentrations of risperidone increased during fluoxetine administration from 12 +/- 9 ng/mL at baseline to 56 +/- 31 at week 4 (p < 0.001), while the levels of 9-OH-risperidone were not significantly affected. After 4 weeks of combined treatment, the levels of the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) increased by 75% (range, 9-204%, p < 0.01) compared with baseline. The mean plasma risperidone/9-OH-risperidone ratio also increased significantly. During the second week of adjunctive therapy, two patients developed Parkinsonian symptoms, which were controlled with anticholinergic medication. These findings indicate that fluoxetine, a potent inhibitor of the cytochrome P450 enzyme CYP2D6 and a less potent inhibitor of CYP3A4, reduces the clearance of risperidone by inhibiting its 9-hydroxylation or alternative metabolic pathways. This interaction may lead to toxic plasma risperidone concentrations. In addition to careful clinical observation, monitoring plasma risperidone levels may be of value in patients given adjunctive therapy with fluoxetine.
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PMID:Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. 1217 43

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100) has been developed to treat subjects with schizophrenia. This drug is mainly excreted in the form of oxidative metabolites. In the present study, identification of p450 forms involved in the metabolism was carried out using human livers and intestinal microsomes (HLM and HIM). Eadie-Hofstee plots for NE-100 disappearance in HLM were biphasic, thus indicating the involvement of at least two p450 forms. The metabolism of NE-100 was mediated with recombinant CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A significant correlation was observed between activities of NE-100 metabolism and dextromethorphan O-demethylation (a specific activity for CYP2D6) or testosterone 6beta-hydroxylation (a specific activity for CYP3A4) in HLM. The activity of NE-100 metabolism was inhibited by approximately 80% by an anti-CYP2D6 antibody and only by quinidine among the p450-selective inhibitors at a low substrate concentration (0.1 microM). In contrast, with a high substrate concentration (10 microM), the activity was inhibited by an anti-CYP3A4 antibody and by ketoconazole. On the other hand, in HIM, the Eadie-Hofstee plots for NE-100 disappearance were monophasic, and the metabolism was strongly inhibited by an anti-CYP3A4 antibody and by ketoconazole but not by other inhibitors used. These results strongly suggest that NE-100 has different profiles regarding metabolism between liver and intestine. During absorption, NE-100 is mainly metabolized by CYP3A4 in the intestine and thereafter by CYP2D6 in the liver in the presence of therapeutic doses.
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PMID:Differences in cytochrome P450 forms involved in the metabolism of N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a novel sigma ligand, in human liver and intestine. 1248 54

Since 1989, several novel antipsychotic drugs have become available for use including clozapine, risperidone, olanzapine, quetiapine and ziprasidone. These agents represent a substantial improvement in the treatment of schizophrenia and related disorders and are considered to have a favourable adverse effect profile relative to traditional antipsychotics. Nonetheless, in rare cases, people have died as a result of taking atypical antipsychotic drugs at therapeutic and supratherapeutic doses. Toxic doses of atypical antipsychotics are highly variable: some patients have died while taking therapeutic doses and others have survived massive overdoses. Toxicity may be increased by coingestion of other agents, particularly drugs with similar metabolic pathways. Atypical antipsychotics are metabolised predominantly by cytochrome p450 (CYP) isoenzymes, particularly CYP1A2 (clozapine and olanzapine), CYP3A4 (clozapine, quetiapine and ziprasidone) and CYP2D6 (olanzapine and risperidone). Concurrent prescription of other drugs that inhibit these isoenzymes may increase the probability of adverse events in patients taking atypical antipsychotics. Deaths due to atypical antipsychotic toxicity are often related to cardiovascular complications, but pulmonary, neurological, endocrine and gastrointestinal complications have also caused fatalities. Prevention and management of atypical antipsychotic overdose are of increased clinical relevance as prescription of these drugs increases.
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PMID:Fatalities associated with therapeutic use and overdose of atypical antipsychotics. 1266 90

Ziprasidone (Geodone), a novel atypical antipsychotic agent, is recently approved for the treatment of schizophrenia. It undergoes extensive metabolism in preclinical species and humans after oral administration, and only a very small amount of administered dose is excreted as unchanged drug. In vitro studies using human liver microsomes have shown that the oxidative metabolism of ziprasidone is mediated primarily by CYP3A4. However, coadministration of ziprasidone with ketoconazole, a CYP3A4 inhibitor, showed only a modest increase in its exposure. Therefore, in vitro metabolism of ziprasidone was investigated in hepatic cytosolic fractions to further understand its clearance mechanisms in preclinical species and humans. The major metabolite from incubation of ziprasidone in cytosolic fractions of rat, dog, and human was characterized by liquid chromatography-tandem mass spectrometry and found to be the product of reductive cleavage. Derivatization and hydrogen/deuterium exchange were used to deduce that the addition of two hydrogen atoms had occurred at the benzisothiazole moiety. Further studies to determine the enzyme involved in the formation of this metabolite are currently in progress. The identification of this novel metabolite in cytosol has clarified the clearance mechanism of ziprasidone in humans and preclinical species.
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PMID:Characterization of a novel metabolite intermediate of ziprasidone in hepatic cytosolic fractions of rat, dog, and human by ESI-MS/MS, hydrogen/deuterium exchange, and chemical derivatization. 1582 Oct 46

The phenotyping cocktail is a practical approach for phenotyping of cytochrome P450 (CYP) enzymes in vivo. In this study, a liquid chromatography-tandem mass spectrometry method using a dual-extraction approach was developed and validated to quantify 5 selective substrates and their metabolites for the simultaneous phenotyping CYPs 1A2, 2C19, 2C9, 2D6, and 3A4 in patient blood samples. The assay was applied in a pilot study of 11 patients with schizophrenia. Five blood samples were collected before and at 1, 2, 4, and 6 hours after administration of a phenotyping cocktail consisting of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam. The method successfully quantitated the CYP enzyme activities without serious side effects in patients. The ratios of metabolite to parent area under the concentration-time curve values were calculated over the 6-hour postdosage to reflect CYP2D6, CYP3A4, and CYP2C9 activities. The ratios of metabolite to parent plasma concentrations were calculated at 4-hour postdosage for CYP1A2 and at 4- or 6-hour postdose for CYP2C19, respectively. The plasma concentration of midazolam at 4 hours was also estimated as another phenotyping index for CYP3A4 activity. The simultaneous assay of all these analytes in a single matrix (plasma) will increase the feasibility of CYP phenotyping in patients.
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PMID:A high-throughput assay using liquid chromatography-tandem mass spectrometry for simultaneous in vivo phenotyping of 5 major cytochrome p450 enzymes in patients. 1930 38


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