Clinical implications of CYP2D6 genetic polymorphism during treatment with antipsychotic drugs.

CYP2D6 is described as the most relevant enzyme in the metabolism of many antipsychotic drugs. Its contribution to the interindividual differences in drug response is reviewed here highlighting its role in the kinetics of antipsychotic drugs and the occurrence of drug interactions. The activity of CYP2D6 is inherited as a monogenetic trait and the CYP2D6 gene appears highly polymorphic in humans. The polymorphic alleles may lead to altered activity of the CYP enzymes causing absent, decreased (poor), or increased (ultrarapid) metabolism that in turn influence the disposition of the antipsychotic drugs. Antipsychotic drug biotransformation is mainly determined by genetic factors mediating CYP2D6 gene polymorphism, however the importance of environmental factors (dietary, smoking, diseases, etc.) is also recognized. Additionally, the potential interaction between CYP2D6 and the endogenous metabolism must be taken into consideration. The present review summarizes the relevance of physiological and environmental factors in CYP2D6 hydroxylation capacity, the inhibition of CYP2D6 activity during treatment, the use of drug/metabolite ratio as a tool to evaluate CYP2D6 hydroxylation capacity in a patient, and the relevance of CYP2D6 for drug plasma concentration and for QTc interval lengthening during treatment with antipsychotic drugs.

The role of cytochrome P450 enzymes in the metabolism of risperidone and its clinical relevance for drug interactions.

In the recent years it has been increasingly recognized that pharmacogenetical factors play an important role in the drug treatment. These factors may influence the appearance of side-effects and drug interactions due to interindividual differences in the activity of metabolizing enzymes. Risperidone in humans is mainly metabolized to 9-hydroxyrisperidone by the polymorphic cytochrome enzyme P450 2D6 (CYP2D6). Plasma concentrations of risperidone and 9-hydroxyrisperidone show large interindividual variability, which may be partly related to the activity of the CYP2D6 enzyme. Around seven percent of Caucasians have a genetically inherited impaired activity of the CYP2D6 enzyme. Debrisoquine metabolic ratio (a marker of CYP2D6 activity) and the number of CYP2D6 active genes have been related to risperidone plasma concentrations among patients during steady-state conditions. A large number drugs have been described to be metabolized by CYP2D6, and it is therefore important to evaluate the clinical significance of the impaired metabolism and possible drug interactions on the enzyme. Since risperidone/9-hydroxyrisperidone ratio strongly correlates with CYP2D6 enzyme activity and the number of CYP2D6 active genes, thus it might be a useful tool in clinical practice to estimate the possible risk of drug interactions due to impaired CYP2D6 enzyme activity. CYP3A4 is the most abundant drug metabolizing enzyme in humans, and in vitro and in vivo results suggest also a role for the enzyme in risperidone metabolism. The consideration of the implication of cytochrome P450 enzymes in risperidone metabolism may help to individualize dose schemes in order to avoid interactions and potentially dangerous side-effects, such us QTc interval lengthening among patients with cardiac risk factors.

CYP2C9 gene and susceptibility to major depressive disorder.

Alteration of monoaminergic neurotransmission has been implicated in the pathophysiology of mood disorders, and CYP2C9 enzyme activity has been shown to be modulated by serotonin in vitro. The present study was aimed at analysing the frequency of CYP2C9 alleles (*1, *2, *3) among patients suffering from major depressive disorder. In all, 70 such suffering psychiatric outpatients were studied. The CYP2C9 genotypes were determined by allele-specific PCR. The CYP2C9*3 allele frequency was higher (P<0.01) among the patients suffering from major depression than in a population of 89 schizophrenic patients (odds ratio=3.3) and 138 healthy volunteers (odds ratio=2.8). The results suggest that CYP2C9 genetic polymorphism may be related to a major depressive disorder due to an alteration in endogenous metabolism, although a linkage between CYP2C9 and some other gene related to depression cannot be ruled out.

[Relationship between clozapine plasma levels and withdrawal symptoms]. / Relación entre los síntomas de discontinuación y los niveles plasmáticos de clozapina.

Discontinuation of clozapine and an attempt to change his medication to sertindol has led to serious psychotic and somatic symptoms in an schizophrenic patient treated with clozapine for five years, however after readministration of clozapine these symptoms rapidly disappeared. To further analyse the case we have developed an HPLC method for the measurement of plasma levels of clozapine and its main metabolite N-desmethyl clozapine in order to monitor the plasma levels of clozapine and to correlate with the clinical symptoms. The present results confirmed that after discontinuation of clozapine no measurable amount of drug or its main metabolite were present in the plasma of the patient. The correlation between the plasma levels of clozapine and the changes in the clinical state of the patient confirmed that the patient's severe psychotic and somatic symptoms were the result of discontinuation of clozapine treatment. The clozapine plasma concentration of the patient reported here was low (100 ng/ml) compared to the generally accepted plasma levels for antipsychotic action of clozapine (350 ng/ml), however the somatic and psychotic clozapine withdrawal symptoms rapidly and completely disappeared.

Relación entre los síntomas de discontinuación y los niveles plasmáticos de clozapina / Relationship between clozapine plasma levels and withdrawal symptoms

La suspensión del tratamiento con clozapina en un intento de introducir sertindol en un paciente esquizofrénico en tratamiento en los últimos 5 años produjo un cuadro intenso de síntomas somáticos y psíquicos, que desaparecieron por readministración de clozapina. Con el fin de analizar la relación entre los niveles plasmáticos de clozapina y su metabolito principal norclozapina con el cuadro clínico, se desarrolló un método por cromatografía líquida de alta resolución (HPLC). Los resultados demuestran que la sintomatología coincide con la desaparición de los niveles plasmáticos de clozapina y su metabolito, y la recuperación con el aumento de éstos. Las concentraciones plasmáticas de clozapina encontradas fueron inferiores a las establecidas como necesarias para la acción antipsicótica de clozapina (350 ng/ml), sin embargo con esta concentración (100 ng/ml) los síntomas tanto psíquicos como somáticos desaparecieron. El presente caso documenta la relación entre la sintomatología de discontinuación de clozapina y los niveles plasmáticos del fármaco y su metabolito principal (AU)

Relationship between risperidone and 9-hydroxy-risperidone plasma concentrations and CYP2D6 enzyme activity in psychiatric patients.

The implication of cytochrome P450 CYP2D6 enzyme activity in the metabolism of the antipsychotic drug risperidone has been reported in vitro and in studies of healthy volunteers. Around 7 % of Caucasians have inherited impaired capacity of this enzyme (poor metabolisers). These subjects might be prone to higher plasma concentrations of risperidone. The aim of the study was to determine the relationship between the debrisoquine metabolic ratio (MR), a marker of CYP2D6 enzyme activity, and risperidone plasma levels in psychiatric patients. A population of 40 Spanish and Hungarian schizophrenic patients was studied. The possible inhibition of CYP2D6 enzyme was also evaluated in a subgroup of patients co-medicated with inhibitors of CYP2D6. The risperidone/9-hydroxy-risperidone ratio correlated significantly with debrisoquine MR (p < 0.001). In patients co-medicated with strong inhibitors of CYP2D6, the plasma levels of risperidone (p < 0.05) and debrisoquine MR (p < 0.01) and risperidone/9-hydroxy-risperidone ratio were higher compared to patients with monotherapy. According to the present data, the evaluation of the risperidone/9-hydroxy-risperidone ratio may reflect the actual enzyme activity of CYP2D6. Therefore, the use of this ratio may help to assess potential pharmacokinetic interactions and to improve risperidone treatment.

Determination of clozapine and its N-desmethyl metabolite by high-performance liquid chromatography with ultraviolet detection.

A rapid high-performance liquid chromatographic method has been developed for the simultaneous determination of the atypical antipsychotic drug clozapine and its principal metabolite, N-desmethyl clozapine in human plasma. After liquid-liquid extraction the compounds were separated in a reversed-phase column and measured by ultraviolet absorption at 230 nm. For both compounds inter-day variations were <3.8%, and, based on a plasma sample volume of 2 ml, the limits of quantification were 25 ng/ml. Analytical interference from coadministered psychoactive drugs and their metabolites was also studied, and no interference was found from the most commonly used antidepressants and antipsychotic drugs. The assay is sufficiently sensitive and easy to use for the analysis of plasma samples in human clinical trials and therapeutic drug monitoring.

Effect of thioridazine dosage on the debrisoquine hydroxylation phenotype in psychiatric patients with different CYP2D6 genotypes.

Sixteen hospitalized white European Spanish psychiatric patients treated with thioridazine alone were studied with respect to CYP2D6 genotype, debrisoquine metabolic ratio (MR), and the plasma levels of thioridazine and its metabolites mesoridazine and sulforidazine. After decreasing the dose of thioridazine the debrisoquine MR and thioridazine plasma levels were redetermined. At the initial determination (regular clinical doses, 20-300 mg/day), 14 of 16 patients (88%) were classified as poor metabolizers of debrisoquine (PMs). However, after complete withdrawal of thioridazine in 10 patients, all 10 became extensive metabolizers except two who were genotypically PMs (*4/*4). The inhibition of debrisoquine metabolism was genotype dependent. All patients with wt/wt genotype treated with a dose 150 mg/d were phenotypically PMs, all patients with wt/*4 genotype treated with a dose of 50 mg/d or greater were PMs. The debrisoquine MR from all dose changes correlated with the dose (p < 0.001) and plasma level (p < 0.001) of thioridazine. The CYP2D6 hydroxylation capacity was inhibited by thioridazine as determined by the debrisoquine MR. This inhibition was reversible by thioridazine withdrawal, and thus seems to be dose dependent and related to CYP2D6 genotype. One must consider the effects of thioridazine dosage on CYP2D6, because it may influence the metabolism of concomitant drugs or produce clinically important adverse effects such as cardiotoxicity. An awareness of this problem and cautious dosage adjustment of other drugs metabolized by the same enzyme are recommended during treatment with thioridazine.

Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity.

Thioridazine is metabolized in humans by CYP2D6 to mesoridazine, which is an active metabolite. Two or more CYP2D6 substrates are seldom given simultaneously to elderly patients because potentially dangerous metabolic interactions may occur. It may be valuable to know the CYP2D6 metabolic capacity of such patients to avoid drug interactions, which depend on the metabolic phenotype. The goal of this study was to evaluate the use of the mesoridazine/thioridazine ratio for the estimation of CYP2D6 enzyme capacity. A sensitive and reliable method has been developed for the determination of thioridazine and its metabolites, mesoridazine and sulforidazine. Commonly used central nervous system (CNS) comedications do not interfere with the method. A group of 27 chronic patients with mental illness receiving monotherapy with thioridazine were studied. There were 23 men and 4 women between 37 and 80 years old (mean +/- SD: 61.2 +/- 10.2). The thioridazine/mesoridazine ratio correlated with the debrisoquine metabolic ratio (r = 0.74, p < 0.001). Therefore, the authors suggest that the measurement of thioridazine and its metabolite might be a useful tool to assess CYP2D6 activity during treatment.

Clozapine withdrawal symptoms after change to sertindole in a schizophrenic patient.

A 30-year-old male patient with paranoid schizophrenia was on clozapine therapy for more than five years. Discontinuation of clozapine and an attempt to change his medication to sertindole has led to serious psychotic and somatic symptoms. After readministration of clozapine the psychotic symptoms rapidly disappeared. The patient was monitored by BPRS and PANSS positive and negative scale. Also clinical and labor parameters of the patient were monitored. The change of his medication from clozapine to sertindole was unsuccessful. This case report suggests that although atypical antipsychotics may be generally different from the classical neuroleptic drugs, there are also significant differences among the atypical antipsychotic drugs in their effects on the receptors of the central nervous system. Therefore the change of clozapine to another atypical antipsychotic medication in the clinical practice should be cross-tapered and the symptoms of withdrawal closely monitored.

Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients.

This study investigated to what extent fluvoxamine affects the pharmacokinetics of thioridazine (THD) in schizophrenic patients under steady-state conditions. Concentrations of THD, mesoridazine, and sulforidazine were measured in plasma samples obtained from 10 male inpatients, aged 36 to 78 years, at three different time points: A, during habitual monotherapy with THD at 88 +/-54 mg/day; B, after addition of a low dosage of fluvoxamine (25 mg twice a day) for 1 week; and C, 2 weeks after fluvoxamine discontinuation. After the addition of fluvoxamine, THD concentrations relative to time point A significantly increased approximately threefold from 0.40 to 1.21 micromol/L (225%) (p < 0.002), mesoridazine concentrations increased from 0.65 to 2.0 micromol/L (219%) (p < 0.004), and sulforidazine levels increased from 0.21 to 0.56 micromol/L (258%) (p < 0.004). The THD-mesoridazine and THD-sulforidazine ratios remained unchanged during the study. Mean plasma THD, mesoridazine, and sulforidazine levels decreased at time point C, but despite fluvoxamine discontinuation for 2 weeks, three patients continued to exhibit elevated concentrations of THD and its metabolites. In conclusion, fluvoxamine markedly interferes with the metabolism of THD, probably at the CYP2C19 and/or CYP1A2 enzyme level. Therefore, clinicians should be aware of the potential for a clinical drug interaction between both compounds, and careful monitoring of THD levels is valuable to prevent the accumulation of the drug and resulting toxicity.

Antibiotic use in 3 European university hospitals.

The use of antibiotic drugs was studied in university teaching hospitals in Tartu, Estonia, Huddinge, Sweden and Badajoz, Spain. Data on drug deliveries to hospital wards during 1992 are presented in defined daily doses (DDD) per 100 bed-days (DDD/100 bed-days). In addition, the time trends of antibiotic use in Tartu University Hospital from 1992 to 1995 are shown. The total amount of antibiotic drugs used for systemic treatment in 1992 was similar in the 3 hospitals, 41 DDD/100 bed-days in Tartu vs. 51 DDD/100 bed-days in Badajoz and 47 DDD/100 bed-days in Huddinge. The antibiotics used most frequently were tetracyclines and aminoglycosides in Tartu, broad-spectrum penicillins and cephalosporins in Badajoz and narrow-spectrum penicillins and cephalosporins in Huddinge. Injectable preparations accounted for one-half of the antibiotics used. Among the medical departments, the total use of antibiotics varied up to 3-fold (from 19 to 61 DDD/100 bed-days), less than among the surgical departments (18-94 DDD/100 bed-days). The frequency of antibiotic use was very similar in departments of similar profile in the 3 hospitals (i.e. in departments of neurology, urology, etc.). The use of antibiotic drugs in intensive care units was twice as high in Huddinge (243 DDD/100 bed-days) as in Badajoz (106 DDD/100 bed-days) and Tartu (135 DDD/100 bed-days) in 1992. In conclusion, the international differences in the use of antibiotics in hospital were not in the frequency of use, but in the predominant prescription preferences in the hospital.