Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIN1Q84FV)
Drug Name			Thioridazine		Drug Info		Mirabegron		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antipsychotic Agents				Urinary Antispasmodics
Structure

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

Drug Name		Thioridazine				Mirabegron
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 Thioridazine caused by Mirabegron mediated inhibition of CYP450 enzyme

Recommended Action
Management		The use of thioridazine with drugs that inhibit CYP450 2D6 is considered contraindicated. Depending on the elimination half-life of these drugs, a considerable waiting period may be appropriate following their discontinuation before thioridazine is initiated. For example, the manufacturer of fluoxetine recommends that thioridazine not be administered within 5 weeks after discontinuing fluoxetine because of the drug's long half-life.

References
1	Abernethy DR, Greenblatt DJ, Steel K, Shader RI "Impairment of hepatic drug oxidation by propoxyphene." Ann Intern Med 97 (1982): 223-4. [PMID: 7103282]
2	Carrillo JA, Ramos SI, Herraiz AG, Llerena A, Agundez JAG, Berecz R, Duran M, Benitez J "Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients." J Clin Psychopharmacol 19 (1999): 494-9. [PMID: 10587283]
3	Fletcher GF, Kazamias TM "Cardiotoxic effects of Mellaril: conduction disturbances and supraventricular arrhythmias." Am Heart J 78 (1969): 135-8. [PMID: 5794785]
4	Glassman AH, Bigger JT Jr "Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death." Am J Psychiatry 158 (2001): 1774-82. [PMID: 11691681]
5	Greendyke RM, Gulya A "Effect of pindolol administration on serum levels of thioridazine, haloperidol, phenytoin, and phenobarbital." J Clin Psychiatry 49 (1988): 105-7. [PMID: 3346197]
6	Greendyke RM, Kanter DR "Plasma propranolol levels and their effect on plasma thioridazine and haloperidol concentrations." J Clin Psychopharmacol 7 (1987): 178-82. [PMID: 3597804]
7	Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SHL "Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans." Clin Pharmacol Ther 60 (1996): 543-53. [PMID: 8941027]
8	Markowitz JS, Wells BG, Carson WH "Interactions between antipsychotic and antihypertensive drugs." Ann Pharmacother 29 (1995): 603-9. [PMID: 7663034]
9	Product Information. Mellaril (thioridazine). Sandoz Pharmaceuticals Corporation, East Hanover, NJ.
10	Product Information. Prozac (fluoxetine). Dista Products Company, Indianapolis, IN.
11	Product Information. Varubi (rolapitant). Tesaro Inc., Waltham, MA.
12	Silver JM, Yudofsky SC, Kogan M, Katz BL "Elevation of thioridazine plasma levels by propranolol." Am J Psychiatry 143 (1986): 1290-2. [PMID: 3766793]
13	Thomas M, Maconochie JG, Fletcher E "The dilemma of the prolonged QT interval in early drug studies." Br J Clin Pharmacol 41 (1996): 77-81. [PMID: 8838432]