Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI1ZI3HNB)
Drug Name			Cimetidine		Drug Info		Halazepam		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiulcer Agents				Antianxiety Agents
Structure

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

Drug Name		Cimetidine				Halazepam
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 Halazepam caused by Cimetidine mediated inhibition of CYP450 enzyme

Recommended Action
Management		The US manufacturers of alprazolam, estazolam and triazolam recommend consideration of a dose reduction when these medicines are co-administered with cimetidine. Use of H2 antagonists and benzodiazepines that are not reported to interact may also be considered. Patients should be advised to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References
1	Abernethy DR, Greenblatt DJ, Divoll M, Moschitto LJ, Harmatz JS, Shader RI "Interaction of cimetidine with the triazolobenzodiazepines alprazolam and triazolam." Psychopharmacology (Berl) 80 (1983): 275-8. [PMID: 6137021]
2	Andersson T, Andren K, Cederberg C, Edvardsson G, Heggelund A, Lundborg P "Effect of omeprazole and cimetidine on plasma diazepam levels." Eur J Clin Pharmacol 39 (1990): 51-4. [PMID: 2276389]
3	Britton ML, Waller ES "Central nervous system toxicity associated with concurrent use of triazolam and cimetidine." Drug Intell Clin Pharm 19 (1985): 666-8. [PMID: 4042860]
4	Desmond PV, Patwardhan RV, Schenker S, Speeg KV "Cimetidine impairs elimination of chlordiazepoxide ( librium) in man." Ann Intern Med 93 (1980): 266-8. [PMID: 7406377]
5	Gough PA, Curry SH, Araujo OE, Robinson JD, Dallman JJ "Influence of cimetidine on oral diazepam elimination with measurement of subsequent cognitive change." Br J Clin Pharmacol 14 (1982): 739-42. [PMID: 7138754]
6	Greenblatt DJ, Abernethy DR, Morse DS, Harmatz JS, Shader RI "Clinical importance of the interaction of diazepam and cimetidine." N Engl J Med 310 (1984): 1639-43. [PMID: 6427609]
7	Greenblatt DJ, Locniskar A, Scavone JM, Blyden GT, Ochs HR, Harmatz JS, Shader RI "Absence of interaction of cimetidine and ranitidine with intravenous and oral midazolam." Anesth Analg 65 (1986): 176-80. [PMID: 2935051]
8	Klotz U, Arvela P, Rosenkranz B "Effect of single doses of cimetidine and ranitidine on the steady-state plasma levels of midazolam." Clin Pharmacol Ther 38 (1985): 652-5. [PMID: 2933205]
9	Klotz U, Reimann I "Delayed clearance of diazepam due to cimetidine." N Engl J Med 302 (1980): 1012-4. [PMID: 6767973]
10	Klotz U, Reimann I "Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam." Eur J Clin Pharmacol 18 (1980): 517-20. [PMID: 6780369]
11	Klotz U, Reimann IW, Ohnhaus EE "Effect of ranitidine on the steady state pharmacokinetics of diazepam." Eur J Clin Pharmacol 24 (1983): 357-60. [PMID: 6305670]
12	Parker WA, MacLachlan RA "Prolonged hypnotic response to triazolam-cimetidine combination in an elderly patient." Drug Intell Clin Pharm 18 (1984): 980-1. [PMID: 6150838]
13	Patwardhan RV, Johnson RF, Sinclair AP, Schenker S, Speeg KV "Lack of tolerance and rapid recovery of cimetidine-inhibited chlordiazepoxide (librium) elimination." Gastroenterology 81 (1981): 547-51. [PMID: 7250643]
14	Ruffalo RL, Thompson JF, Segal J "Cimetidine-benzodiazepine drug interaction." Am J Hosp Pharm 38 (1981): 1365-6. [PMID: 6116430]
15	Salonen M, Aantaa E, Aaltonen L, Kanto J "Importance of the interaction of midazolam and cimetidine." Acta Pharmacol Toxicol (Copenh) 58 (1986): 91-5. [PMID: 2939688]
16	Wilson CM, Robinson FP, Thompson EM, Dundee JW, Elliott P "Effect of pretreatment with ranitidine on the hypnotic action of single doses of midazolam, temazepam and zopiclone. A clinical study." Br J Anaesth 58 (1986): 483-6. [PMID: 2938611]
17	Wrighton SA, Ring BJ "Inhibition of human CYP3A catalyzed 1'-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine." Pharm Res 11 (1994): 921-4. [PMID: 7937537]
18	Pourbaix S, Desager JP, Hulhoven R, Smith RB, Harvengt C "Pharmacokinetic consequences of long term coadministration of cimetidine and triazolobenzodiazepines, alprazolam and triazolam, in healthy subjects." Int J Clin Pharmacol Ther Toxicol 23 (1985): 447-51. [PMID: 2864320]
19	Sanders LD, Whitehead C, Gildersleve CD, Rosen M, Robinson JO "Interaction of H2-receptor antagonists and benzodiazepine sedation. A double-blind placebo-controlled investigation of the effects of cimetidine and ranitidine on recovery after intravenous midazolam." Anaesthesia 48 (1993): 286-92. [PMID: 8494127]