Is clozapine metabolized by 2d6?
Clozapine is an atypical antipsychotic metabolized by CYP1A2, CYP2D6, and CYP2C19 enzymes.
What is a CYP1A2 inhibitor?
CYP1A2 is a 515-residue protein with a molecular mass of 58,294 Dal. In particular, several therapeutic drugs including antofloxacin, carbamazepine, dihydralazine, furafylline, isoniazid, rofecoxib, clorgyline, thiabendazole, and zileuton are mechanism-based inhibitors of CYP1A2.
Is clozapine a CYP3A4 inhibitor?
Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering clozapine tablets concomitantly with drugs that are inducers or inhibitors of these enzymes.
How is clozapine metabolized?
Clozapine is metabolized in the liver by various cytochrome P450 enzymes (CYP1A2, CYP3A4, CYP2C19, CYP2D6) and flavin-containing monooxygenase 321,22; however, CYP1A2 and CYP3A4 enzymes seem to be primarily responsible for the main metabolic pathways, forming two major metabolites, the pharmacologically active …
Is clozapine an enzyme inhibitor?
CYP1A2 is the main CYP enzyme in clozapine metabolism. Other CYP enzymes involved in clozapine metabolism include CYP2C19, CYP2D6 and CYP3A4. Strong inhibitors of CYP1A2 include ciprofloxacin, fluvoxamine and enoxacin, and these can increase clozapine levels as much as 5-10 fold.
What enzyme metabolizes clozapine?
Clozapine undergoes complex hepatic metabolism involving multiple cytochrome P450 (CYP) isoforms, the enzyme variants that catalyse biotransformation reactions (Fig. 1). It is primarily metabolised by the CYP1A2 isoform, but CYP3A4 and to a lesser extent CYP2C9, CYP2C19 and CYP2D6 are also involved [15].
Is clozapine A inhibitor?
Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate.
Does clozapine cause metabolic syndrome?
Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy.
Which drugs are enzyme inhibitors?
Examples of enzyme-inhibiting agents are cimetidine, erythromycin, ciprofloxacin, and isoniazid.
Is clozapine narrow therapeutic index?
Clozapine provides a 50%–60% response rate in refractory schizophrenia but has a narrow therapeutic index and is susceptible to pharmacokinetic interactions, particularly with strong inhibitors or inducers of cytochrome P450 (CYP) 1A2.
How is clozapine metabolized in the liver?
In all nine liver microsomal preparations investigated, clozapine was extensively metabolized to the stable products desmethylclozapine (range 19%-27.2%), N-oxide (1.5-20.5%) and three polar metabolites (0-20.8%), and was bioactivated to a protein-reactive metabolite (0.6-2.1%).
Do CYP2D6 inhibitors affect metabolism of clozapine?
In an in vitromicrosome experiment, the CYP2D6 inhibitors quinidine and dextromethorphan influenced the metabolism of clozapine and reduced the generation of minor metabolic products as shown by HPLC, but did not change the amount of N-desmethylclozapine or clozapine n-oxide [66].
Does clozapine N-oxide inhibit CYP2C19?
Clozapine n-oxide inhibits the CYP2C19 mediated metabolism of s-mephenytoin in vitro[70]. Potentially then clozapine n-oxide may inhibit CYP2C19 metabolism of PPIs. Moderate or weak CYP1A2 or CYP3A4 inducers are also discussed in the drug label, with the suggestion to increase dose if lack of efficacy is observed.
What is clozapine used to treat?
Clozapine is an atypical antipsychotic and the gold standard for treatment refractory schizophrenia (TRS), i.e. for whom at least two traditional antipsychotics have been ineffective [1].