Pharmacologic Profile of Perphenazine's Metabolites

Abstract

The authors have previously reported that in elderly patients treated with low doses of perphenazine, few extrapyramidal symptoms (EPS) developed in those who were not poor CYP2D6 metabolizers. The authors hypothesized that this atypical side effect profile is due to perphenazine's principal metabolite, n-dealkylperphenazine (DAPZ), which is usually present in vivo at concentrations 1.5 to 2 times that of the parent drug. Perphenazine, DAPZ, and 7-hydroxyperphenazine affinities were examined in vitro by competition-binding analysis to isolated human receptors expressed in transfected cell lines. Perphenazine and metabolite effects were examined in vivo in 54 older patients who were treated with perphenazine, at a target dose of 0.1 mg/kg, for 10 to 17 days. Drug concentrations were determined by high-performance liquid chromatography with electrochemical detection. In in vitro binding studies, DAPZ demonstrated a higher affinity for serotonin-2A receptors than for dopamine-2 receptors to an extent comparable to that of some atypical neuroleptic agents. In contrast, perphenazine and 7-hydroxyperphenazine demonstrated a higher affinity for dopamine-2 receptors than for serotonin-2A receptors. The mean +/- SD concentrations in the 54 subjects were the following: perphenazine, 1.5 +/- 1.4 ng/mL; DAPZ, 2.0 +/-1.6 ng/mL; and 7-hydroxyperphenazine, 0.8 +/- 1.9 ng/mL. The mean +/- SD quotient for the DAPZ/perphenazine concentration was 1.7 +/- 1.1 and for the 7-hydroxyperphenazine/perphenazine was 0.54 +/-1.6. EPS onset was not correlated with the perphenazine concentration, the metabolite concentrations, the DAPZ/perphenazine quotient, or the 7-hydroxyperphenazine/perphenazine quotient. Despite a moderately atypical receptor-binding profile, DAPZ does not seem to moderate perphenazine effects in vivo in older patients. This outcome likely reflects the low potency of DAPZ for dopamine-2 and serotonin-2A receptors relative to the potency of perphenazine for these receptors. Further exploration of atypical properties of DAPZ should include de novo administration of this metabolite in animal models.

CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6–serotonin–dopamine crosstalk revisited

“…Although the steady-state plasma concentration of N-dealkylperphenazine, on average, is 1.7-fold higher than perphenazine, the in-vitro inhibition potency of this metabolite for the human dopamine D2 receptor (DRD2) is at least 20-fold lesser than the parent compound, perphenazine [38]. 7-OH-perphenazine steady-state concentration in patients is at half the concentration of perphenazine [38]. Moreover, in-vitro inhibition potency of 7-OH-perphenazine for the DRD2 is about 20% less than perphenazine [38].…”

“…This is particularly the case with metabolites that display a higher activity than the parent compound [16]. Perphenazine is metabolized primarily by N-dealkylation with a loss of hydroxyethyl group, ring hydroxylation at position 7 and oxidation of the sulfur atom in the form of perphenazine sulfoxide [18,19,[38][39][40][41][42]. N-dealkylated perphenazine is eliminated as a sulfoxide whereas 7-OH-perphenazine is excreted in the urine as a glucuronide [41,42].…”

“…On the other hand, the bulky perphenazine metabolites (the glucuronidated form and the sulfoxide) are devoid of clinical activity [18][19][20]. Although the steady-state plasma concentration of N-dealkylperphenazine, on average, is 1.7-fold higher than perphenazine, the in-vitro inhibition potency of this metabolite for the human dopamine D2 receptor (DRD2) is at least 20-fold lesser than the parent compound, perphenazine [38]. 7-OH-perphenazine steady-state concentration in patients is at half the concentration of perphenazine [38].…”

Recommendations for the Monitoring of Serum Concentrations of Antipsychotic Drugs in the Treatment of Schizophrenia

“…Perphenazine, an FGA with a relatively low incidence of extrapyramidal side effects, has been shown to be most effective at concentrations of 0.6-2.4 ng/mL, with such side effects rarely occurring at concentrations below 5 ng/mL. 5 It is illegal to post this copyrighted PDF on any website.…”

Meet the relatives: a reintroduction to the clinical pharmacology of ‘typical’ antipsychotics (Part 1)

“…2 mg) can produce drowsiness without hypotension, even when administered intramuscularly, giving it a safety margin over chlorpromazine (Musey 1986). It has no significant anticholinergic action (Sweet 2000;Chew 2008) and although well known to promote EPS in higher doses, its relatively good EPS tolerability at low to medium doses probably reflects the fact that its major metabolite, N-dealkyl perphenazine, which with chronic use attains blood levels 1.5-2 times those of the parent drug, shows modest antimuscarinic (M 1 ) binding (Sweet 2000). This might therefore be a drug to start and hold low in order to allow build-up of the metabolite in the expectation of an anti-EPS effect as doses rise.…”