To examine the genetic factors influencing clozapine kinetics in vivo, 75 patients treated with clozapine were genotyped for CYPs and ABCB1 polymorphisms and phenotyped for CYP1A2 and CYP3A activity. CYP1A2 activity and dose-corrected trough steady-state plasma concentrations of clozapine correlated significantly (r = -0.61; P = 1 x 10), with no influence of the CYP1A2*1F genotype (P = 0.38). CYP2C19 poor metabolizers (*2/*2 genotype) had 2.3-fold higher (P = 0.036) clozapine concentrations than the extensive metabolizers (non-*2/*2). In patients comedicated with fluvoxamine, a strong CYP1A2 inhibitor, clozapine and norclozapine concentrations correlate with CYP3A activity (r = 0.44, P = 0.075; r = 0.63, P = 0.007, respectively). Carriers of the ABCB1 3435TT genotype had a 1.6-fold higher clozapine plasma concentrations than noncarriers (P = 0.046). In conclusion, this study has shown for the first time a significant in vivo role of CYP2C19 and the P-gp transporter in the pharmacokinetics of clozapine. CYP1A2 is the main CYP isoform involved in clozapine metabolism, with CYP2C19 contributing moderately, and CYP3A4 contributing only in patients with reduced CYP1A2 activity. In addition, ABCB1, but not CYP2B6, CYP2C9, CYP2D6, CYP3A5, nor CYP3A7 polymorphisms, influence clozapine pharmacokinetics

Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients. The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications. The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy. Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations

Kasuistik om en 31 Õrig kvinde, hvis serum clozapin falder efter seponering af coffeintabletter og anden coffeinindtag.

Olanzapine has previously been shown to have predominant metabolism by cytochrome (CYP) P450 1A2. Caffeine has been shown to provide an accurate phenotypic probe for measuring CYP1A2 activity. The purpose of this study is to determine if a significant correlation exists between olanzapine disposition and caffeine metabolic ratios. Subjects were phenotyped for CYP1A2 activity with caffeine probe methodology. After 200-mg caffeine administration, blood (4 h), saliva (6 and 10 h), and urine (8 h total) were collected for high-performance liquid chromatography (HPLC) analysis of caffeine and its metabolites.CYP1A2 activity was measured as plasma (PMR(4 h)), saliva (SMR(6 h) and SMR(10 h)), and three urinary metabolic (UMR1(8 h), UMR2(8 h), and UMR3(8 h)) ratios. Each of the 14 healthy nonsmokers (13 male) received a single 10 mg olanzapine dose after which blood was collected for HPLC determination of olanzapine concentrations at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 h postdose. Olanzapine pharmacokinetic parameters in this study were similar to those previously published. All caffeine metabolic ratios (PMR(4 h), SMR(6 h), SMR(10 h), UMR1(8 h), and UMR2(8 h)) significantly correlated with each other (p <0.001) except for UMR3(8 h), which did not correlate. A significant correlation (p <0.05) was also found between olanzapine clearance and PMR(4 h) (r=0.701), SMR(6 h) (r=0.644), SMR(10 h) (r=0.701), UMR1(8 h) (r=0.745), and UMR2(8 h) (r=0.710). A negative correlation was observed between olanzapine clearance and UMR3(8 h) (r=-0.029, p=NS). A significant correlation was found between olanzapine clearance and various caffeine metabolic ratios. Interpatient variability in CYP1A2 activity may explain the wide interpatient variability in olanzapine disposition. Compounds that modulate CYP1A2 activity may be expected to alter olanzapine pharmacokinetics accordingly

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity

AIMS: To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers. METHODS: This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg day-1, range: 400-1000 mg day-1 ). Serum concentrations of clozapine and its metabolites desmethyl-clozapine and clozapine-N-oxide were measured during a 48 h period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored. RESULTS: A 19% increase in mean clozapine AUC(0,infinity) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0, 12h) for desmethyl-clozapine and AUC(0,12h) for clozapine (-18%), and between AUC(0,12h) for clozapine-N-oxide and AUC(0,12h) for clozapine (-23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0, 12h) for desmethyl-clozapine/AUC(0,12h) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively). CONCLUSIONS: These results suggest that caffeine in daily doses of 400-1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals

Both clozapine (CLZ) and caffeine are CYP1A2 substrates. This study raises the hypothesis of whether caffeine withdrawal from the diet alters the metabolism and/or clinical status of patients receiving CLZ. Seven schizophrenic patients (six men and one woman) receiving monotherapy with CLZ at 271+/-102 mg/day (3.73+/-1.4 mg/kg) participated in the study. CLZ, norclozapine (NOR), and clozapine-N-oxide (NOX) were assayed in plasma by high-performance liquid chromatography at three different time points: A, with concomitant intake of caffeine from the diet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was determined by means of a urinary caffeine test. After a caffeine-free diet for 5 days, CLZ concentrations relative to time point A decreased from 486 to 306 ng/mL (-47%) (p < 0.02), NOX levels decreased from 66 to 49 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increased from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to initial figures at time point C. The NOR/CLZ ratio was significantly correlated to the CYP1A2 index (rs = 0.96, p < 0.0005). In conclusion, changes in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be medically supervised, and the monitoring of CLZ and metabolite levels may be warranted. Furthermore, in those patients who receive therapy with CLZ, the NOR/CLZ ratio may provide an additional and valuable estimate of CYP1A2 activity

Kasuistik over en 39-Õrig mand med paranoid schizophreni. Patienten har de sidste 20 Õr vµret bruger af mange forskellige neuroleptika. Han skifter nu til clozapin og tager medicinen med 2 kopper kaffe som sµdvanligt. Hver gang han medicineres oplever han akutte kortvarige psykoser. Det samme hvis han tager clozapin og Cola Light, men ikke hvis han tager den med coffeinfri Cola Light.

BACKGROUND: Metabolism of clozapine is complex and not fully understood. Pharmacokinetic interactions with other drugs have been described but, in some cases, their mechanism is unknown. METHOD: Published trials and case reports relevant to the human metabolism of clozapine and to suspected pharmacokinetic interactions were reviewed. RESULTS: Metabolism of clozapine appears to be largely controlled by the function of the hepatic cytochrome p450IA2 (CYPIA2). Compounds which induce CYPIA2 activity (carbamazepine, tobacco smoke) may reduce plasma clozapine levels. Inhibitors of CYPIA2 (caffeine, erythromycin) have the opposite effect. Drugs which inhibit the hepatic cytochrome p4502D6 (CYP2D6) have also been reported to elevate plasma clozapine levels. The mechanism of this interaction is unclear. CONCLUSIONS: The co-administration of clozapine and compounds reported to alter its metabolism should be avoided where possible. A host of other interactions can be predicted and so caution should be exercised when co-administering drugs which affect the function of CYPIA2 and CYP2D6. The pharmacokinetics of clozapine require further investigation so that its safe use can be assured