Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI4SRTUO6)
Drug Name			Diltiazem		Drug Info		Aminophylline		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antihypertensive Agents				Bronchodilators
Structure

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

Drug Name		Diltiazem				Aminophylline
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 Aminophylline caused by Diltiazem mediated inhibition of CYP450 enzyme

Recommended Action
Management		Clinical monitoring of patient response and tolerance and serum theophylline levels is recommended. Patients should be advised to report any signs of theophylline toxicity including nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat to their physicians.

References
1	Abernethy DR, Egan JM, Dickinson TH, Carrum G "Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans." J Pharmacol Exp Ther 244 (1988): 994-9. [PMID: 3252045]
2	Christopher MA, Harman E, Hendeles L "Clinical relevance of the interaction of theophylline with diltiazem or nifedipine." Chest 95 (1989): 309-13. [PMID: 2914480]
3	Nafziger AN, May JJ, Bertino JS Jr "Inhibition of theophylline elimination by diltiazem therapy." J Clin Pharmacol 27 (1987): 862-5. [PMID: 3429693]
4	Ohashi K, Sakamoto K, Sudo T, Tateishi T, Fujimura A, Shiga T, Ebihara A "Effects of diltiazem and cimetidine on theophylline oxidative metabolism." J Clin Pharmacol 33 (1993): 1233-7. [PMID: 8126258]
5	Smith SR, Haffner CA, Kendall MJ "The influence of nifedipine and diltiazem on serum theophylline concentration-time profiles." J Clin Pharm Ther 14 (1989): 403-8. [PMID: 2584285]
6	Soto J, Sacristan JA, Alsar MJ "Diltiazem treatment impairs theophylline elimination in patients with bronchospastic airway disease." Ther Drug Monit 16 (1994): 49-52. [PMID: 8160255]
7	Upton RA "Pharmacokinetic interactions between theophylline and other medication (Part II)." Clin Pharmacokinet 20 (1991): 135-50. [PMID: 1709398]