Clozapine metabolism

Nefazodone had minimal effects on clozapine metabolism when co-administered in six patients mean clozapine concentrations rose by 4% and norclozapine concentrations by 16% (168). 

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. 

Facciola G, Avenoso A, Spina E, Perucca E. Inducing effect of phenobarbital on clozapine metabolism in patients with chronic schizophrenia. Ther Drug Monit 1998 20(6) 628-30. 

Increased clozapine serum concentrations have been reported with erythromycin (199,200) and can cause adverse effects (SEDA-21, 55). However, in 12 healthy men who took a single dose of clozapine 12.5 mg alone or in combination with a daily dose of erythromycin 1.5 g, the metabolism of clozapine was not altered (201). This confirms that CYP3A4 is a relatively minor pathway for clozapine metabolism, in contrast to CYP1A2. 

Because of the risk of seizures with higher clozapine tissue concentrations, inhibition interactions with clozapine are potentially significant. In particular, fluvoxamine has been reported to increase clozapine serum concentrations by an average of two- to threefold and up to fivefold. Fluoxetine and erythromycin may increase clozapine serum concentrations in some patients, but to a lesser degree. Mean clozapine serum concentrations are reported to be 32% lower in smokers compared with nonsmokers." Carbamazepine may also induce clozapine metabolism and lead to lower serum concentrations. ... 

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).

IS CYP3A4 4 CYP3A4Vma Clozapine metabolized bv Q5AR model... 

El CYP2C19 4 CYP2C19Km Clozapine metabolized by QSAR model... 

The conclusion is that the cytochrome P450 isoenzyme CYP3A4 is of only minor importance in clozapine metabolism, and that because no interaction takes place between clozapine and itraconazole or ketoconazole, both it and other inhibitors of CYP3A4 can be used with clozapine. However, note that raised clozapine levels have been attributed to treatment with the CYP3A4 inhibitor, erythromycin, see Clozapine + Erythromycin , p.747. 

MookhoekEJ, Loonen AJM. Retrospective evaluation of the effect of omeprazole on clozapine metabolism. Pharm WorldSci (2004) 26, 180-2. 

Markowitz JS, Gill HS, Devane CL, Mintzer JE. Fluoroquinolone inhibition of clozapine metabolism./I 0997) 153, 881. 

Brouwers EE, Sohne M, Kuipers S, van Gorp EC, Schellens JH, Koks CH, Beijnen JH, Huitema AD. Ciprofloxacin strongly inhibits clozapine metabolism two case reports. Clin Drug Investig 2009 29(1) 59-63. 

---