Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIQZ8MPSB)
Drug Name			Pimozide		Drug Info		Lorcaserin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antipsychotic Agents				Anorexiants
Structure

Mechanism of Pimozide-Lorcaserin Interaction (Severity Level: Major)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Pimozide				Lorcaserin
Mechanism		CYP450 2D6 substrate				CYP450 2D6 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 2D6				× Structure Sequence MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQLRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVFLARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDKAVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKVLRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVADLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVIHEVQRFGDIVPLGVTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHFLDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGVFAFLVSPSPYELCAVPR
		Gene Name		CYP2D6
		Uniprot ID		CP2D6_HUMAN
		KEGG Pathway		hsa:1565
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants. Click to Show/Hide
Mechanism Description		Decreased metabolism of Pimozide caused by Lorcaserin mediated inhibition of CYP450 enzyme

Recommended Action
Management		Due to the narrow therapeutic index of pimozide, concomitant use of pimozide in combination with moderate inhibitors of CYP450 2D6 should preferably be avoided if possible. Otherwise, close monitoring for the development of electrocardiographic abnormalities, extrapyramidal reactions (i.e., acute dystonic reactions, tardive dyskinesia, akathisia, Parkinson-like symptoms), and hypotension is recommended if concurrent use is required. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope. The manufacturers consider the use of pimozide with potent CYP450 2D6 inhibitors such as fluoxetine, paroxetine, and quinidine to be contraindicated.

References
1	Canadian Pharmacists Association.
2	Cerner Multum, Inc. "Australian Product Information.".
3	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
4	EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports.".
5	Product Information. Orap Tablets (pimozide). Gate Pharmaceuticals, Sellersville, PA.
6	Product Information. Varubi (rolapitant). Tesaro Inc., Waltham, MA.