Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIFK4SJZN)
Drug Name			Bicalutamide		Drug Info		Cilostazol		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antineoplastics				Vasodilator Agents
Structure

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

Drug Name		Bicalutamide				Cilostazol
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 Cilostazol caused by Bicalutamide mediated inhibition of CYP450 enzyme

Recommended Action
Management		Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 and/or 2C19 inhibitor is added to or withdrawn from cilostazol therapy, and the dosage adjusted as necessary. Patients should be advised to contact their physician if they experience adverse effects of cilostazol such as dizziness, nausea, diarrhea, bleeding, or irregular heartbeat.

References
1	Hedaya MA, El-Afify DR, El-Maghraby GM "The effect of ciprofloxacin and clarithromycin on sildenafil oral bioavailability in human volunteers." Biopharm Drug Dispos 27 (2006): 103-10. [PMID: 16372380]
2	Herrlin K, Segerdahl M, Gustafsson LL, Kalso E "Methadone, ciprofloxacin, and adverse drug reactions." Lancet 356 (2000): 2069-70. [PMID: 11145498]
3	McLellan RA, Drobitch RK, Monshouwer M, Renton KW "Fluoroquinolone antibiotics inhibit cytochrome P450-mediated microsomal drug metabolism in rat and human." Drug Metab Dispos 24 (1996): 1134-8. [PMID: 8894516]
4	Product Information. Pletal (cilostazol). Otsuka American Pharmaceuticals, Rockville, MD.
5	Sawant RD "Rhabdomyolysis due to an uncommon interaction of ciprofloxacin with simvastatin." Can J Clin Pharmacol 16 (2009): e78-9. [PMID: 19151423]
6	Shahzadi A, Javed I, Aslam B, et al. "Therapeutic effects of ciprofloxacin on the pharmacokinetics of carbamazepine in healthy adult male volunteers." Pak J Pharm Sci 24 (2011): 63-8. [PMID: 21190921]
7	Sriwiriyajan S, Samaeng M, Ridtitid W, Mahatthanatrakul W, Wongnawa M "Pharmacokinetic interactions between ciprofloxacin and itraconazole in healthy male volunteers." Biopharm Drug Dispos 32 (2011): 168-74. [PMID: 21360715]
8	Suri A, Bramer SL "Effect of omeprazole on the metabolism of cilostazol." Clin Pharmacokinet 37 (1999): 53-9. [PMID: 10702887]
9	Suri A, Forbes WP, Bramer SL "Effects of CYP3A inhibition on the metabolism of cilostazol." Clin Pharmacokinet 37 (1999): 61-8. [PMID: 10702888]