Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI90MCZAE)
Drug Name			Bicalutamide		Drug Info		Aripiprazole		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antineoplastics				Antipsychotic Agents
Structure

Mechanism of Bicalutamide-Aripiprazole Interaction (Severity Level: Moderate)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Bicalutamide				Aripiprazole
Mechanism		CYP450 3A4 inhibitor				CYP450 3A4 substrate
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 Aripiprazole caused by Bicalutamide mediated inhibition of CYP450 enzyme

Recommended Action
Management		Pharmacologic response to aripiprazole should be monitored more closely whenever a CYP450 3A4 and/or 2D6 inhibitor is added to or withdrawn from therapy, and the aripiprazole dosage adjusted as necessary. The manufacturer recommends that aripiprazole dosage be reduced to one-half the normal dosage during concomitant administration with ketoconazole or quinidine, and additional dosage adjustments be made based on clinical evaluation.

References
1	Cerner Multum, Inc. "Australian Product Information.".
2	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
3	Goodnick PJ, Jerry J, Parra F "Psychotropic drugs and the ECG: focus on the QTc interval." Expert Opin Pharmacother 3 (2002): 479-98. [PMID: 11996627]
4	Kane JM, Carson WH, Saha AR, et al. "Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder." J Clin Psychiatry 63 (2002): 763-71. [PMID: 12363115]
5	Keck PE Jr, Marcus R, Tourkodimitris S, et al. "A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania." Am J Psychiatry 160 (2003): 1651-8. [PMID: 12944341]
6	Nelson S, Leung JG "Torsades de Pointes After Administration of Low-Dose Aripiprazole (February)." Ann Pharmacother (2013):. [PMID: 23362038]
7	Pigott TA, Carson WH, Saha AR, Torbeyns AF, Stock EG, Ingenito GG "Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study." J Clin Psychiatry 64 (2003): 1048-56. [PMID: 14628980]
8	Product Information. Abilify (aripiprazole). Bristol-Myers Squibb, Princeton, NJ.