Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: their influence on pharmacogenetic dosing algorithms.

Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9*2,*3 and *8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9*1/*1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings.

The chemical defensive system in the pathobiology of idiopathic environment-associated diseases.

Chemical defensive system consisting of bio-sensoring, transmitting, and responsive elements has been evolved to protect multi-cellular organisms against environmental chemical insults (xenobiotics) and to maintain homeostasis of endogenous low molecular weight metabolites (endobiotics). Both genetic and epigenetic defects of the system in association with carcinogenesis and individual sensitivity to anti-tumor therapies have been intensely studied. Recently, several non-tumor human pathologies with evident environmental components such as rather rare functional syndromes (multiple chemical sensitivity, chronic fatigue, Persian Gulf, and fibromyalgia now collectively labeled as idiopathic environmental intolerances) and common diseases (vitiligo and systemic lupus erythematosus) have become subjects of the research on the impaired metabolism and detoxification of xenobiotics and endogenous toxins. Here, we collected and critically reviewed epidemiological, genetic, and biochemical data on the involvement and possible role of cytochrome P450 super family enzymes, glutathione-S-transferase isozymes, catechol-O-methyl-transferase, UDP-glucuronosyl transferases, and proteins detoxifying inorganic and organic peroxides (catalase, glutathione peroxidase, and peroxiredoxin) in the above pathologies. Genetic predisposition assessed mainly by single nucleotide polymorphism and gene expression analyses revealed correlations between defects in genes encoding xenobiotic-metabolizing and/or detoxifying enzymes and risk/severity of these syndromes/diseases. Proteome analysis identified abnormal expression of the enzymes. Their functions were affected epigenetically leading to metabolic impairment and, as a consequence, to the negative health outcomes shared by some of these pathologies. Data obtained so far suggest that distinct components of the chemical defensive system could be suitable molecular targets for future pathogenic therapies.

A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy.

The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.

Severe phenytoin intoxication in a subject homozygous for CYP2C9*3.

A 31-year-old woman who had a severe head injury was treated with oral phenytoin (100 mg 3 times a day) to prevent posttraumatic seizures. On day 10 of phenytoin treatment, 3 hours after the morning dose, the patient manifested neurologic signs compatible with phenytoin intoxication. Thus drug serum concentrations were monitored daily for 12 days. The elimination half-life was 103 hours, namely, about 5 times longer than the mean value generally quoted (22 hours). In the absence of any acquired predisposing factor for phenytoin toxicity, genetic mutations in the cytochrome P450 (CYP) enzymes responsible for phenytoin metabolism (CYP2C9 and CYP2C19) were suspected. Genotyping revealed that the patient was homozygous for the CYP2C9*3 allele (CYP2C9*3/*3) and heterozygous for the CYP2C19*2 allele (CYP2C19*1/*2). In view of the markedly reduced metabolic activity of CYP2C*3 in comparison with the wild-type enzyme (about one fifth) and of the minor role of CYP2C19 in phenytoin metabolism, it is likely that CYP2C9*3 mutation was largely responsible for drug overdose.

Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population.

AIMS: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect the therapeutic outcome during treatment with several drugs. The distribution of variant CYP2C9 alleles was therefore investigated in an Italian and an Ethiopian population. METHODS: Allele-specific PCR analysis was carried out in order to determine the frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 157 Italians and 150 Ethiopians. RESULTS: The frequencies of CYP2C9*1 (80%), CYP2C9*2 (11%) and CYP2C9*3 (9%) found in the Italian population were similar to other Caucasian groups. However in the Ethiopian population CYP2C9*1, CYP2C9*2 and CYP2C9*3 were present at a frequency of 94, 4 and 2% respectively. The 95% confidence intervals in CYP2C9*1, CYP2C9*2 and CYP2C9*3 between Italians and Ethiopians were 0.098, 0.176, 0.040, 0.098 and 0.040, 0.098, respectively. CONCLUSIONS: Our results indicate that the Ethiopian population has a unique relative distribution of the CYP2C9 alleles, which is not similar to any other ethnic group hitherto described.

Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes.

The antipsychotic agent risperidone, is metabolized by different cytochrome P-450 (CYP) enzymes, including CYP2D6, to the active 9-hydroxyrisperidone, which is the major metabolite in plasma. Two enantiomers, (+)- and (-)-9-hydroxyrisperidone might be formed, and the aim of this study was to evaluate the importance of CYP2D6 and CYP3A4/CYP3A5 in the formation of these two enantiomers in human liver microsomes and in recombinantly expressed enzymes. The enantiomers of 9-hydroxyrisperidone were analyzed with high pressure liquid chromatography using a chiral alpha-1 acid glycoprotein column. A much higher formation rate was observed for (+)-9-hydroxyrisperidone than for (-)-9-hydroxyrisperidone in microsomes prepared from six individual livers. The formation of (+)-9-hydroxyrisperidone was strongly inhibited by quinidine, a potent CYP2D6 inhibitor, whereas ketoconazole, a CYP3A4 inhibitor, strongly inhibited the formation of (-)-9-hydroxyrisperidone. Recombinant human CYP2D6 produced only (+)-9-hydroxyrisperidone, whereas a lower formation rate of both enantiomers was detected with expressed CYP3A4 and CYP3A5. In vivo data from 18 patients during treatment with risperidone indicate that the plasma concentration of the (+)-enantiomer is higher than that of the (-)-enantiomer in extensive metabolizers of CYP2D6. These findings clearly suggest that CYP2D6 plays a predominant role in (+)-9-hydroxylation of risperidone, the major metabolic pathway in clinical conditions, whereas CYP3A catalyzes the formation of the (-)-9-hydroxymetabolite. Further studies are required to evaluate the pharmacological/toxic activity of both enantiomers.

Plasma concentrations of risperidone and 9-hydroxyrisperidone during combined treatment with paroxetine.

SUMMARY: The effects of paroxetine on steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) were studied in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized using risperidone therapy (4-8 mg/d) also received paroxetine (20 mg/d) for 4 weeks. During paroxetine administration, mean plasma concentrations of risperidone increased significantly (P < 0.01), whereas levels of 9-OH-risperidone decreased slightly but not significantly. After 4 weeks of paroxetine treatment, the sum of the concentrations of risperidone and 9-OH-risperidone (active moiety) increased significantly by 45% (P < 0.05) over baseline. The mean plasma risperidone/9-OH-risperidone ratio was also significantly modified (P < 0.001) during paroxetine treatment. The drug combination was generally well tolerated with the exception of one patient who developed Parkinsonian symptoms in the second week of adjunctive therapy. In this patient total plasma levels of risperidone and its active metabolite increased by 62% during paroxetine co-administration. The authors' findings indicate that paroxetine, a potent inhibitor of CYP2D6, may impair the elimination of risperidone, primarily by inhibiting CYP2D6-mediated 9-hydroxylation and to a lesser extent by simultaneously affecting the further metabolism of 9-OH-risperidone or other pathways of risperidone biotransformation. Careful clinical observation and possibly monitoring of plasma risperidone levels may be useful whenever paroxetine is co-administered with risperidone.

Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia.

RATIONALE: Evaluation of relationships between serum antipsychotic drug concentrations and clinical response may provide valuable information for rational dosage adjustments. For risperidone, this relationship has been little investigated to date. OBJECTIVE: To assess the relationship between plasma concentrations of risperidone and its active 9-hydroxy-metabolite (9-OH-risperidone) and clinical response in schizophrenic patients who experienced an acute exacerbation of the disorder. METHODS: Forty-two patients (30 males, 12 females, age 24-60 years) were given risperidone at dosages ranging from 4 to 9 mg/day for 6 weeks. The design of the study was open and risperidone dosage could be adjusted individually according to clinical response. Steady-state plasma concentrations of risperidone and its 9-hydroxymetabolite were measured after 4 and 6 weeks using a specific HPLC assay. Psychopathological state was assessed at baseline and at weeks 2, 4, and 6 by means of the positive and negative syndrome scale (PANSS), and patients were considered responders if they showed a greater than 20% reduction in total PANSS score at final evaluation compared with baseline. RESULTS: Mean plasma concentrations of risperidone, 9-OH-risperidone, and active moiety (sum of risperidone and 9-OH-risperidone concentrations) did not differ between responders (n = 28) and non-responders (n = 14). No correlation between plasma levels and percent decrease in total PANSS score was found for risperidone (rs = -0.187, NS), 9-OH-risperidone (rs = 0.246, NS), and active moiety (rs = 0.249, NS). Active moiety concentrations in plasma were higher (P < 0.001) in patients developing clinically significant parkinsonian symptoms (n = 7) than in those with minimal (n = 7) or no drug-induced parkinsonism (n = 28). CONCLUSIONS: In chronic schizophrenic patients experiencing an acute exacerbation of the disorder, plasma levels of risperidone and its active metabolite correlate with the occurrence of parkinsonian side effects, whereas no significant correlation appears to exist with the degree of clinical improvement.

Newer antipsychotics: comparative review of drug interactions.

The new atypical antipsychotics are subject to drug-drug interactions with other psychotropic agents or with medications used in the treatment of concomitant somatic illnesses - usually at the pharmacokinetic or pharmacodynamic level. While novel antipsychotics are unlikely to interfere with the elimination of other drugs, coadministration of inhibitors or inducers of the cytochrome P450 isoenzymes responsible for their metabolism may modify plasma antipsychotic concentrations, leading to potentially (clinically) significant effects. Newer antipsychotics have binding affinity at a variety of neurotransmitter receptors and might therefore be involved in pharmacodynamic interactions when given in combination with agents acting on the same systems. Differences in the interaction potential among the current novel antipsychotics may be predicted based on their pharmacokinetic and pharmacodynamic properties. Avoidance of unnecessary polytherapy, knowledge of the interaction profiles of individual agents and careful individualization of dosage based on close evaluation of clinical response and possibly plasma drug concentrations are essential to prevent and minimize potentially adverse drug interactions in patients receiving newer antipsychotics.

Enantioselective analysis of citalopram and metabolites in adolescents.

Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent despite its increasing use in these age groups. The aim of this study was to investigate a group of adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites desmethylcitalopram and didesmethylcitalopram. Moreover, the authors studied the genotypes for the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19 in relation to the different enantiomers. The S/R ratios of citalopram and desmethylcitalopram found in this study of 19 adolescents were similar to studies involving older patients. The concentrations of the R-(-)- and S-(+)-enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies, the R-(-)-enantiomer (distomer) being the major enantiomer. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the CYP2C19 enzyme.

No effect of reboxetine on plasma concentrations of clozapine, risperidone, and their active metabolites.

The effect of reboxetine on steady-state plasma concentrations of the atypical antipsychotics clozapine and risperidone was studied in 14 patients with schizophrenia or schizoaffective disorder with associated depressive symptoms. Seven patients stabilized on clozapine therapy (250-500 mg/day) and seven receiving risperidone (4-6 mg/day) were given additional reboxetine (8 mg/day). After 4 weeks of reboxetine therapy, mean plasma concentrations of clozapine, norclozapine, and risperidone active moiety (sum of concentrations of risperidone and 9-hydroxyrisperidone) increased slightly but not significantly by 5%, 2%, and 10%, respectively. The mean plasma clozapine/norclozapine and risperidone/9-hydroxyrisperidone ratios were not modified during reboxetine treatment. Reboxetine coadministration with either clozapine or risperidone was well tolerated. These findings indicate that reboxetine has minimal effects on the metabolism of clozapine and risperidone and may be added safely to patients receiving maintenance treatment with these two antipsychotics.

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.

Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics.

RATIONALE: Monitoring plasma clozapine concentrations may play a useful role in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still controversial. OBJECTIVE: The purpose of this study was to assess the relationship between plasma concentrations of clozapine and its weakly active metabolite norclozapine and clinical response in patients with schizophrenia resistant to conventional neuroleptics. METHODS: Forty-five patients, 35 males and ten females, aged 19-65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were measured at week 12 by a specific HPLC assay. Psychopathological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score of 35 or less. RESULTS: Mean plasma clozapine concentrations were higher in responders (n=18) than in non-responders (n=27) (472+/-220 versus 328+/-128 ng/ml, P<0.01), whereas plasma norclozapine levels did not differ between the two groups (201+/-104 versus 156+/-64 ng/ml, NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (r(s)=0.371, P<0.02), but not for norclozapine (r(s)=0.162, NS). A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67% and specificity 78%. The incidence of side effects was twice as high at clozapine concentrations above 350 ng/ml compared with lower concentrations (38% versus 17%). CONCLUSIONS: These results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concentrations of 350 ng/ml or greater would require in some patients use of unrealistically high dosages and imply an excessive risk of side effects. Increasing dosage to achieve plasma levels above 350-400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations.

Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline.

The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.

CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects in schizophrenic patients.

OBJECTIVE: In order to evaluate whether poor metabolizers (PM) of debrisoquine are overrepresented among patients with acute dystonic reactions and chronic movement disorders associated with the administration of antipsychotic drugs, the CYP2D6 genotype was determined in schizophrenic patients. METHODS: Allele status for CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 as well as gene duplication was determined by allele-specific PCR, long-PCR and restriction fragment length polymorphism analysis (RFLP) in 119 schizophrenic patients (99 males and 20 females). All subjects were treated with antipsychotics metabolized, at least partially, by this isozyme. Sixty-three of the patients (52.9%) had a history of extrapyramidal side effects (EPS), while 56 (47.1%) had not experienced such problems (controls). RESULTS: Sixty-five patients (54.6%) were homozygous for a functional CYP2D6*1 allele, 44 (37.0%) were heterozygous for detrimental alleles, and 4 (3.4%), who carried two detrimental alleles, were classified as PM. In six patients (5.0%) duplication of a functional CYP2D6 gene was found, and they were consequently classified as ultrarapid metabolizers (UM). Homo- and heterozygous extensive metabolizers (EM) as well as UM were equally distributed between patients with and without EPS, whereas all the PM had a history of EPS. No significant differences in allele frequencies between the two groups were found. CONCLUSION: Although the results cannot be considered conclusive due to the small number of PM patients in our study, the PM genotype may be a predisposing factor for antipsychotic-induced EPS. Knowledge of the CYP2D6 genotype, before starting antipsychotic therapy, might be useful in identifying subjects at risk of developing EPS.

No effect of the new antidepressant reboxetine on CYP2D6 activity in healthy volunteers.

The effect of the new antidepressant reboxetine on the activity of the cytochrome P450 (CYP) 2D6 isoenzyme was investigated in 10 healthy volunteers using dextromethorphan as a model CYP2D6 substrate. Each volunteer received a single 30 mg oral dose of dextromethorphan on three different occasions separated by an interval of at least 4 weeks: a) in a control session; b) after 1 week of treatment with reboxetine, 8 mg/day; and c) after 1 week of treatment with paroxetine (an inhibitor of CYP2D6 activity) 20 mg/day. Urine was collected over the next 8 hours for the determination of the dextromethorphan/dextrorphan metabolic ratio. All subjects were classified as extensive metabolizers (EM) with a dextromethorphan/dextrorphan ratio < 0.3. There were no notable changes in the urinary dextromethorphan/dextrorphan ratio in the reboxetine phase as compared to the control session. By contrast, there was a statistically significant increase in the metabolic ratio in the paroxetine phase (p < 0.001), with 4 subjects switching to poor metabolizer (PM) phenotype. These results suggest that reboxetine is unlikely to cause clinically significant interactions with substrates of CYP2D6.

Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders.

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.

Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone.

The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of risperidone to its major active metabolite, 9-hydroxyrisperidone (9-OH-risperidone), has been documented after single oral doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the steady-state plasma concentrations of risperidone and 9-OH-risperidone was investigated. Thirty-seven schizophrenic patients on monotherapy with risperidone, 4-8 mg/day, were genotyped by RFLP and PCR for the major functional variants of the CYP2D6 gene. Steady state plasma levels of risperidone and 9-OH-risperidone were analysed by HPLC. Based on the genotype analysis, three patients were classified as ultrarapid metabolizers (UM) with an extra functional CYP2D6 gene, 16 were homozygous extensive metabolizers (EM), 15 heterozygous EM and three poor metabolizers (PM). The median steady-state plasma concentration-to-dose (C/D) ratios of risperidone were 0.6, 1.1, 9.7 and 17.4 nmol/l per mg in UM, homozygous EM, heterozygous EM and PM, respectively, with statistically significant differences between PM and the other genotypes (P < 0.02). The C/D of 9-OH-risperidone also varied widely but was not related to the genotype. The risperidone/9-OH-risperidone ratio was strongly associated with the CYP2D6 genotype, with the highest ratios in PM (median 0.79). Heterozygous EM also had significantly higher ratios than homozygous EM (median value 0.23 versus 0.04; P < 0.01) or UM (median 0.03; P < 0.02). No significant differences were found in the C/D of the sum of the plasma concentrations of risperidone and 9-OH-risperidone between the genotype groups. In conclusion, the steady-state plasma concentrations of risperidone and the risperidone/9-OH-risperidone ratio are highly dependent on the CYP2D6 genotype. However, as risperidone and 9-OH-risperidone are considered to have similar pharmacological activity, the lack of relationship between the genotype and the sum of risperidone and 9-OH-risperidone indicates that the CYP2D6 polymorphism may be of limited importance for the clinical outcome of the treatment.

Elevation of plasma carbamazepine concentrations by ketoconazole in patients with epilepsy.

The effect of ketoconazole (200 mg/d orally for 10 days) on the plasma concentrations of carbamazepine (CBZ) and its active metabolite carbamazepine-10,11-epoxide (CBZ-E) was assessed in eight patients with epilepsy stabilized on CBZ therapy. Administration of ketoconazole was associated with a significant increase in plasma CBZ concentrations (from 5.6 +/- 1.9 to 7.2 +/- 2.9 micrograms/ml on day 10 [means +/- SD, P < 0.02]), whereas plasma concentrations of CBZ-E were unchanged. After ketoconazole was discontinued, plasma CBZ levels decreased to pretreatment values. This interaction was probably mediated by an inhibiting action of ketoconazole on cytochrome CYP3A4, the main enzyme responsible for CBZ metabolism.