Perphenazine metabolism

Phenothiazines The phenothiazines (PTZs) undergo extensive metabolism. Metabolic routes include S-oxidation, aromatic hydroxylation, N-dealkylation, N-oxidation, and a combination of these processes. Chlorpromazine, for example, possesses 168 possible metabolites, a large proportion of which are pharmacologically active compounds. The development of an HPLC assay capable of resolving a large number of these metabolites is virtually impossible and assays that permit the simultaneous determination of the parent compound and a selected number of active metabolites must suffice. The PTZ group of compounds includes chlorpromazine, thioridazine, fluphenazine, and perphenazine. 

Pakkenberg, H., Fog, R., 8c Nilakantan, B. (1973). The long-term effect of perphenazine enanthate on the rat brain Some metabolic and anatomical observations. Psycho-pharmacologia (Berlin), 29, 329-336. 

Perphenazine doubled clozapine concentrations in a 46-year-old male smoker, with paradoxical myoclonus, hypersalivation, and worsening of psychosis (261). The mechanism of this effect is not known perphenazine is a substrate for CYP2D6, but that is not important in the metabolism of clozapine. 

CLOZAPINE, HALOPERIDOL, PERPHENAZINE, RISPERIDONE IMATINIB Imatinib may cause t plasma concentrations of these drugs with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

IMATINIB 1. ANTIARRHYTHMICS -flecainide, mexiletine, propafenone 2. ANTIDEPRESSANTS - fluoxetine, paroxetine, TCAs, trazodone, venlafaxine 3. ANTIPSYCHOTICS -clozapine, haloperidol, perphenazine, risperidone, thioridazine 4. BETA-BLOCKERS - metoprolol, propanolol, timolol 5. DONEPEZIL 6. METHAMPHETAMINE Imatinib may cause t plasma concentrations of these drugs, with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

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... 

Pollock et al. observed that elderly patients treated with perphenazine who were efficient CYP2D6 metabolizers developed fewer EPS than patients who were poor 2D6 me-tabolizers (431). They hypothesized that the principal perphenazine metabolite, N-dealkyl perphenazine (DNPZ) might be responsible... 

Citalopram does not interfere with the metabolism of APDs. At a dose of 40 mg/day, citalopram caused no significant changes in plasma concentrations of chlorpromazine, clozapine, haloperidol, perphenazine, thioridazine, or zuclopenthixol. Anecdotal data suggest that citalopram may increase the serum levels of levomepromazine. 

Carbamazepinewasfound to decrease the plasma levels of phenothiazines by as much as 50% (described with chlorpromazine, perphenazine, and fluphenazine). It has been reported to decrease the serum levels of clozapine by about60-85% due to its hepatic cytochrome P450 (CYP) enzyme-inducing properties. Loxapine may induce carbamazepine metabolism. Carbamazepine has been shown to reduce the plasma levels of risperidone by as much as 50%, while it increases olanzapine clearance by 44% and reduces its half-life by 20%. Carbamazepine increases aripiprazole metabolism through CYP3A4 induction. Thus, the aripiprazoie dose should be doubled. 

ARIPIPRAZOLE, CLOZAPINE, HALOPERIDOL, PERPHENAZINE, RISPERIDONE, SERTINDOLE SSRIs Possible t plasma concentrations of these antipsychotics Inhibition of CYP2D6-mediated metabolism of these drugs. The clinical significance of this depends upon whether alternative pathways of metabolism of these substrates are also inhibited by co-adminis-tered drugs. The risk is theoretically greater with clozapine, haloperidol and olanzapine because their CYPl A2-mediated metabolism Is also Inhibited by SSRIs Warn patients to report T side-effects of these drugs, and consider reducing the dose of the antipsychotic... 

Hansen LB, Larsen N-E. Metabolic interaction between perphenazine and disulfiram. Lancet (1982) ii, 1472,... 

Cooper SF, Dugal R, Elie R, Albert J-M. Metabolic interaction between amitriptyline and perphenazine in psychiatric patients. Prog Neuropsychopharmacol (1979) 3, 369-76. 

Metabolism A prospective, naturalistic study of 809 patients that compared 10 antipsychotics found there were no significant relationships between any of the antipsychotic drugs and increased waist circumference, HOMA-IR or LDL-cholesterol levels [54 ]. Hypertriglyceridemia was associated with clozapine, reduced HDL-cholesterol with both clozapine and olanzapine, hypertension with perphenazine, and hyperglycaemia inversely with ziprasidone and positively with haloperidol. 

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