A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Orap Pharmacology, Pharmacokinetics, Studies, Metabolism - Pimozide
Orap Pharmacology, Pharmacokinetics, Studies, Metabolism - Pimozide
CLINICAL PHARMACOLOGY
Pharmacodynamic Actions
ORAP (pimozide) is an orally active antipsychotic drug product
which shares with other antipsychotics the ability to blockade dopaminergic
receptors on neurons in the central nervous system. Although its exact mode
of action has not been established, the ability of pimozide to suppress motor
and phonic tics in Tourette's Disorder is thought to be a function of its dopaminergic
blocking activity. However, receptor blockade is often accompanied by a series
of secondary alterations in central dopamine metabolism and function which may
contribute to both pimozide's therapeutic and untoward effects. In addition,
pimozide, in common with other antipsychotic drugs, has various effects on other
central nervous system receptor systems which are not fully characterized.
Metabolism and Pharmacokinetics
More than 50% of a dose of pimozide is absorbed after oral
administration. Based on the pharmacokinetic and metabolic profile, pimozide
appears to undergo significant first pass metabolism. Peak serum levels occur
generally six to eight hours (range 4-12 hours) after dosing.
Pimozide is extensively metabolized, primarily by N-dealkylation
in the liver. This metabolism is catalyzed mainly by the cytochrome P450 3A
(CYP 3A) enzymatic system and to a lesser extent, by cytochrome P450 1A2 (CYP
1A2). Two major metabolites have been identified, 1-(4-piperidyl)-2-benzimidazolinone
and 4,4-bis(4-fluorophenyl) butyric acid. The antipsychotic activity of these
metabolites is undetermined. The major route of elimination of pimozide and
its metabolites is through the kidney.
The mean serum elimination half-life of pimozide in schizophrenic
patients was approximately 55 hours. There was a 13-fold interindividual difference
in the area under the serum pimozide leveltime curve and an equivalent degree
of variation in peak serum levels among patients studied. The significance of
this is unclear since there are few correlations between plasma levels and clinical
findings.
Effects of food and disease upon the absorption, distribution,
metabolism and elimination of pimozide are not known. Effects of concomitant
medication on pimozide metabolism are described in the CONTRAINDICATIONS
section.
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