Clozapine metabolizing enzymes

Some of the genetic aspects of clozapine-induced agranulocytosis have been evaluated (143). Polymorphisms of specific clozapine metabolizing enzyme systems were determined in 31 patients with agranulocytosis and in 77 without. Genotyping of a recently discovered G-463 A polymorphism of the myeloperoxidase gene and CYP2D6 showed no evidence of an association. 

Dettling M, Sachse C, Muller-Oerlinghausen B, Roots I, Brockmoller J, Rolfs A, Cascorbi I. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry 2000 33(6) 218-20. 

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. 

Recall that one of the key drug-metabolizing enzymes is the cytochrome P450 (CYP450) enzyme called 1A2. Two atypical antipsychotic drugs are substrates of 1A2, namely olanzapine and clozapine. That means that when they are given con-... 

Phenytoin induces hepatic microsomal drug-metabolizing enzymes and thus reduces concentrations of haloperidol (663,664), thioridazine (664), and tiotixene (665). In two patients phenytoin reduced plasma clozapine concentrations and worsened psychosis (666). 

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... 

Fig. 3. Simple interaction network for the drug clozapine, three P450 enzymes for which clozapine is a substrate, the enzymatic clozapine metabolic reaction catalyzed by the enzymes, and the clozapine metabolite resulting from the reaction. Compound-protein and compound-reaction interactions are shown. Compounds are represented by hexagons, proteins by different solid shapes representing different classes of compound, and enzymatic reactions by rectangles. Edges (interactions) between nodes (network objects) are shown as unidirectional arrows with a mechanism of interaction represented by letters in hexagonal boxes over the arrows (6 binding, Zcatalysis).

Inhibits metabolizing enzymes (caffeine inhibits CYPl A2, which metabolizes clozapine). Inhibition of CYP by ginkgo t alpha-1 effects of risperidone. Valerian may worsen the sedative properties of haloperidol. Hops and phenothiazine have been associated with hyperthermia in dogs... 

Induction of metabolizing enzymes (green tea may induce CYP1A2, which metabolizes clozapine)... 

Baker GB. Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn... 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Phenytoin, an enzyme inducer, can reduce clozapine plasma levels. There have been two reported cases of risperidone causing an increase in clozapine plasma levels however, because this agent is not an inhibitor of 1A2, the mechanisms for this increase are unclear. Nefazodone administered with clozapine has had minimal effects on clozapine s metabolism (329). 

The heme iron in the peroxidase is oxidized by the peroxide from III+ to V4- in compound I. The compound I is reduced by two sequential one-electron transfer processes giving rise to the original enzyme. A substrate-free radical is in turn generated. This may have toxicological implications. Thus the myeloperoxidase in the bone marrow may catalyze the metabolic activation of phenol or other metabolites of benzene. This may underlie the toxicity of benzene to the bone marrow, which causes aplastic anemia (see below and chap. 6). The myeloperoxidase found in neutrophils and monocytes may be involved in the metabolism and activation of a number of drugs such as isoniazid, clozapine, procainamide, and hydralazine (see below). In in vitro systems, the products of the activation were found to be cytotoxic in vitro. 

Because of the frequency of co-administration of benzodiazepines with neuroleptic drugs, it is important to consider possible adverse effects that can result from such combinations. In a brief review, emphasis has been placed on pharmacokinetic interactions between neuroleptic drugs and benzodiazepines, as much information on their metabolic pathways is emerging (166). Thus, the enzyme CYP3A4, which plays a dominant role in the metabolism of benzodiazepines, also contributes to the metabolism of clozapine, haloperidol, and quetiapine, and neuroleptic drug plasma concentrations can rise. Intramuscular levomepromazine in combination with an intravenous benzodiazepine has been said to increase the risk of airways obstruction, on the basis of five cases of respiratory impairment the doses of levomepromazine were higher in the five cases that had accompanying airways obstruction than in another 95 patients who did not (167). 

Other N-oxidized substrates include mianserin and clozapine both catalyzed by CYP1A2 and CYP3A4. Because the products are identical to those produced by flavin monooxygenases (FMOs), enzymatic studies are required to identify which enzyme system is active during in vivo metabolism. 

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