Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI07GT2K8)
Drug Name			Pimozide		Drug Info		Troleandomycin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antipsychotic Agents				Antibiotics
Structure

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

Drug Name		Pimozide				Troleandomycin
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 3A4				× Structure Sequence MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
		Gene Name		CYP3A4
		Uniprot ID		CP3A4_HUMAN
		KEGG Pathway		hsa:1576
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, 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). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981). Click to Show/Hide
Mechanism Description		Decreased metabolism of Pimozide caused by Troleandomycin mediated inhibition of CYP450 enzyme

Recommended Action
Management		The use of pimozide with telithromycin or macrolide antibiotics is considered contraindicated by the manufacturers, although azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4.

References
1	Amsden GW "Macrolides versus azalides: a drug interaction update." Ann Pharmacother 29 (1995): 906-17. [PMID: 8547740]
2	Desta Z, Kerbusch T, Flockhart DA "Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6)." Clin Pharmacol Ther 65 (1999): 10-20. [PMID: 9951426]
3	Desta Z, Soukhova N, Flockhart DA "In Vitro Inhibition of Pimozide N-Dealkylation by Selective Serotonin Reuptake Inhibitors and Azithromycin." J Clin Psychopharmacol 22 (2002): 162-168. [PMID: 11910261]
4	Flockhart DA, Drici MD, Kerbusch T, et al "Studies on the mechanism of a fatal clarithromycin-pimozide interaction in a patient with tourette syndrome." J Clin Psychopharmacol 20 (2000): 317-24. [PMID: 10831018]
5	Krahenbuhl S, Sauter B, Kupferschmidt H, Krause M, Wyss PA, Meier PJ "Case report: reversible QT prolongation with torsades de pointes in a patient with pimozide intoxication." Am J Med Sci 309 (1995): 315-6. [PMID: 7771501]
6	Product Information. Ketek (telithromycin). Aventis Pharmaceuticals, Bridgewater, NJ.
7	Product Information. Orap Tablets (pimozide). Gate Pharmaceuticals, Sellersville, PA.
8	European Agency for the Evaluation of Medicinal Products. Committee for Proprietary Medicinal Products "European Public Assessment Report Ketek (telithromycin) (Rev. 2) ".