About this pathway
Background
Pimozide is a typical antipsychotic FDA approved for treatment of Tourette’s disorder who have failed other treatments. The FDA label has a warning for QT prolongation [Article:23059146]. The cardiac electrophysiological effects of pimozide are concentration dependent therefore variants that affect pharmacokinetics may be important [Article:11584332]. Pimozide is on the FDA biomarkers list with caution for dosing in adult and pediatric CYP2D6 poor metabolizers [Article:23059146]. The label also contraindicates strong inhibitors of CYP2D6 and CYP3A4.
Metabolism
Pimozide is mainly metabolized to three products: 6-hydroxypimozide, 5-hydroxypimozide and 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI) accounting for approximately 90% of biotransformation [Article:32847865]. The relative amounts of the different metabolites produced by human liver microsomes were related to relative abundance of CYP2D6 and CYP3A4 [Article:32847865]. CYP2D6 primarily produces the 5-hydroxypmiozide metabolite, with some formation of 6-hydroxypimozide whereas CYP3A4 primarily generates DHPBI [Article:32847865].
Absorption
In vitro transport studies across Caco-2 cells demonstrated that pimozide is transported by ABCB1 [Article:33119612]. In addition sertraline or aripiprazole significantly decreased the efflux ratio of pimozide in vitro providing a possible mechanism of drug drug interactions that were fatal in a reported case study [Article:33119612][Article:25819538].
Reactions & interactions (13)
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Biochemical Reaction
pimozide → 6-hydroxypimozide
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Biochemical Reaction
pimozide → DHPBI
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Biochemical Reaction
pimozide → 5-hydroxypimozide
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Catalysis
ABCB1 → Transport
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Catalysis
CYP2D6 → Biochemical Reaction
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Catalysis
CYP3A4 → Biochemical Reaction
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Catalysis
CYP3A5 → Biochemical Reaction
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Catalysis
CYP3A4 → Biochemical Reaction
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Catalysis
CYP3A7 → Biochemical Reaction
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Catalysis
CYP3A5 → Biochemical Reaction
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Catalysis
CYP2D6 → Biochemical Reaction
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Catalysis
CYP3A4 → Biochemical Reaction
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Transport
pimozide → pimozide
Edit history (1)
- 2021-01-12 Create