Clozapine caffeine

Smoking cessation, with or without nicotine substitutes, may alter response to concomitant medication in ex-smokers. Smoking may affect alcohol, benzodiazepines, beta-adrenergic blockers, caffeine, clozapine, fluvoxamine, olanzapine, tacrine, theophylline, clorazepate, lidocaine (oral), estradiol, flecanide, imipramine, heparin, insulin, mexiletine, opioids, propranolol, catecholamines, and cortisol. 

Substrates Inhibitors Inducers CYP1A2 Acetaminophen, caffeine, clozapine, imipramine, theophylline, propranolol Most fluoroquinolone antibiotics, fluvoxamine, cimetidine Tobacco smoking, charcoal-broiled foods, cruciferous vegetables, omeprazole... 

Splice variant Decreased activity Caffeine, clozapine Uncertain... 

I With fluvoxamine (due to cytochrome P450-1A2 inhibition) caffeine, clozapine, theophylline. 

Bertilsson, L. et al. (1994). Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Br. J. Clin. Pharmacol, 38,471-3. 

Raaska, K., Raitasuo, V., Laitila, J. Neuvonen, P. J. (2004). Effect of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations in hospitalised patients. Pharmacol. Toxicol, 94, 13-18. 

Bertilsson, L., Carrillo, J.A., Dahl, M.L., Llerena, A., Aim, C., Bondesson, U., Lindstrom, L., Rodriguez dela Rubia, I., Ramos, S. and Benitez, J. (1994) Clozapine disposition covaries with CYP1A2 activity determined hy a caffeine test. British Journal of Clinical Pharmacology, 38 (5), 471 173. 

Drugs that may interact with clozapine include caffeine, SSRIs, benzodiazepines, risperidone, CYP1A2 induces/inhibitors, CYP3A4 inhibitors, phenobarbital, and ritonavir. 

Clozapine is principally metabolized to N -desmethylclozapine (norclozapine). It is also metabolized to and n-oxide, other hydroxyl metabolites, and a protein-reactive metabolite. The n-oxide can be converted back to clozapine. The enzyme responsible for the metabolism of clozapine to norclozapine is the cytochrome P450 1A2 enzyme (325). This is consistent with a study showing that caffeine, a marker for 1A2, is cleared in relationship to the conversion of clozapine to norclozapine ( 326). Discontinuation of coffee intake can decrease the clozapine plasma levels by more than 50%, and increasing caffeine intake can produce a reemergence of the side effects (e.g., drowsiness, excess salivation). Additionally, smoking, which induces 1A2, lowers clozapine plasma levels. Fluvoxamine, an inhibitor of 1A2, dramatically increases plasma levels, and on occasion, adverse effects are seen ( 327). This phenomenon can lead to clozapine intoxication in patients on high doses of fluvoxamine. 

A2 Tertiary amine TCAs, duloxetine, theophylline, phenacetin, TCAs (demethylation), clozapine, diazepam, caffeine Fluvoxamine, fluoxetine, moclobemide, ramelteon Tobacco, omeprazole... 

Cyt 1A2 metabolizes clozapine common substrates - amitriptyline, clomipramine, propranolol, theophylline, warfarin, caffeine. Common inhibitors - fluvoxamine, paroxetine. 

Ozdemir V, Kalow W, Posner P, Collins EJ, Kennedy JL, Tang BK, Albers LJ, Reist C, Roy R, Walkes W, Afra P. CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite steady-state concen-trationin patients with schizophrenia. J Clin Psychopharmacol 2001 21 398-407. 

Such approaches have been used successfully to demonstrate the induction of CYP1A2 by smoking (42). In addition, this study showed that oral contraceptives produce a small but significant inhibition of CYP1A2. Urinary metabolic ratios have also been used to show that oral AUC of clozapine was correlated with caffeine N-3-demethylation (59), a finding supported by some recent in vitro data, which has shown that clozapine N-demethylation is mediated by CYP1A2 (60). 

Caffeine has been associated with changes in the metabolism of clozapine (SEDA-20, 50 SEDA-22, 61). Seven schizophrenic patients taking clozapine monotherapy participated in a study of the effects of caffeine withdrawal from the diet (247). After a caffeine-free diet for 5 days, clozapine plasma concentrations fell by 50%. The authors suggested that schizophrenic patients treated with clozapine should have their caffeine intake medically supervised, and that monitoring of concentrations of clozapine and its metabolite may be warranted. 

The effects of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations have been examined in 12 patients in a randomized, placebo-con-trolled, crossover study (248). Serum clozapine concentration increased, probably because of inhibition of CYP1A2. However, the effect was minor in most of the patients, although some individuals may be more sensitive to this interaction, owing for example to genetic factors. 

Carrillo JA, Herraiz AG, Ramos SI, Benitez J. Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients. J Clin Psychopharmacol 1998 18(4) 311-6. 

CLOZAPINE CAFFEINE t clozapine levels Possibly metabolism via CYP1A2 Warn patients to avoid wide variations in caffeine intake once established on clozapine... 

Caffeine 2. Chaste tree 3. Green tea 4. Plantain 1. Lithium 2. Phenothiazines (e.g. chlorpromazine, promazine, levomepromazine, pericyazine, pipotiazine, fluphenazine, perphenazine, trifluphenazine) 3. Clozapine L blood lithium levels with 1 clinical effects. 1 effects of phenothiazines Unknown mechanism (caffeine) Contains dopamine agonists (chaste tree) Induction of metabolizing enzymes (green tea may induce CYP1A2, which metabolizes clozapine) l absorption from the gut (plantain may l absorption of lithium) Be aware. Caffeine withdrawal may precipitate lithium toxicity, so avoid sudden caffeine withdrawal. Avoid concomitant use if possible... 

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