Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIQ5OARV6)
Drug Name			Caffeine		Drug Info		Norfloxacin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antihypertensive Agents				Antibiotics
Structure

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

Drug Name		Caffeine				Norfloxacin
Mechanism		CYP450 1A2 substrate				CYP450 1A2 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 1A2				× Structure Sequence MALSQSVPFSATELLLASAIFCLVFWVLKGLRPRVPKGLKSPPEPWGWPLLGHVLTLGKNPHLALSRMSQRYGDVLQIRIGSTPVLVLSRLDTIRQALVRQGDDFKGRPDLYTSTLITDGQSLTFSTDSGPVWAARRRLAQNALNTFSIASDPASSSSCYLEEHVSKEAKALISRLQELMAGPGHFDPYNQVVVSVANVIGAMCFGQHFPESSDEMLSLVKNTHEFVETASSGNPLDFFPILRYLPNPALQRFKAFNQRFLWFLQKTVQEHYQDFDKNSVRDITGALFKHSKKGPRASGNLIPQEKIVNLVNDIFGAGFDTVTTAISWSLMYLVTKPEIQRKIQKELDTVIGRERRPRLSDRPQLPYLEAFILETFRHSSFLPFTIPHSTTRDTTLNGFYIPKKCCVFVNQWQVNHDPELWEDPSEFRPERFLTADGTAINKPLSEKMMLFGMGKRRCIGEVLAKWEIFLFLAILLQQLEFSVPPGVKVDLTPIYGLTMKHARCEHVQARLRFSIN
		Gene Name		CYP1A2
		Uniprot ID		CP1A2_HUMAN
		KEGG Pathway		hsa:1544
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). 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:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable). Click to Show/Hide
Mechanism Description		Decreased metabolism of Caffeine caused by Norfloxacin mediated inhibition of CYP450 enzyme

Recommended Action
Management		Patients using caffeine-containing products should be advised that increased adverse effects such as headache, tremor, restlessness, nervousness, insomnia, tachycardia, and blood pressure increases may occur during coadministration with quinolones that inhibit CYP450 1A2. Caffeine intake should be limited when taking high dosages of these quinolones. If an interaction is suspected, other quinolones such as gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, and ofloxacin may be considered, since they are generally believed to have little or no effect on CYP450 1A2 or have been shown not to interact with caffeine.

References
1	Carbo ML, Segura J, De la Torre R, et al "Effect of quinolones on caffeine disposition." Clin Pharmacol Ther 45 (1989): 234-40. [PMID: 2920498]
2	Carrillo JA, Benitez J "Clinically significant pharmacokinetic interactions between dietary caffeine and medications." Clin Pharmacokinet 39 (2000): 127-53. [PMID: 10976659]
3	Fuhr U, Wolff T, Harder S, Schymanski P, Staib AH "Quinolone inhibition of cytochrome P-450 dependent caffeine metabolism in human liver microsomes." Drug Metab Dispos 18 (1990): 1005-10. [PMID: 1981505]
4	Harder S, Fuhr U, Staib AH, Wolf T "Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations." Am J Med 87 (1989): 89-91. [PMID: 2589393]
5	Harder S, Staib AH, Beer C, Papenburg A, Stille W, Shah PM "4-Quinolones inhibit biotransformation of caffeine." Eur J Clin Pharmacol 35 (1988): 651-6. [PMID: 2853056]
6	Healy DP, Polk RE, Kanawati L, Rock DT, Mooney ML "Interaction between oral ciprofloxacin and caffeine in normal volunteers." Antimicrob Agents Chemother 33 (1989): 474-8. [PMID: 2729942]
7	Healy DP, Schoenle JR, Stotka J, Polk RE "Lack of interaction between lomefloxacin and caffeine in normal volunteers." Antimicrob Agents Chemother 35 (1991): 660-4. [PMID: 2069371]
8	Kinzig-Schippers M, Fuhr U, Zaigler M, et al "Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2." Clin Pharmacol Ther 65 (1999): 262-74. [PMID: 10096258]
9	Mahr G, Sorgel F, Granneman GR, et al "Effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine." Clin Pharmacokinet 22 (1992): 90-7. [PMID: 1319876]
10	Nicolau DP, Nightingale CH, Tessier PR, et al. "The effect of fleroxacin and ciprofloxacin on the pharmacokinetics of multiple dose caffeine." Drugs 49 Suppl 2 (1995): 357-9. [PMID: 8549360]
11	Polk RE "Drug-drug interactions with ciprofloxacin and other fluoroquinolones." Am J Med 87 (1989): s76-81. [PMID: 2686430]
12	Product Information. Cipro (ciprofloxacin). Bayer, West Haven, CT.
13	Product Information. Noroxin (norfloxacin). Merck & Co, Inc, West Point, PA.
14	Product Information. Penetrax (enoxacin). Rhone-Poulenc Rorer, Collegeville, PA. (1993):.
15	Product Information. Raxar (grepafloxacin). Glaxo Wellcome, Research Triangle Park, NC.
16	Staib AH, Stille W, Dietlein G, et al. "Interaction between quinolones and caffeine." Drugs 34 Suppl 1 (1987): 170-4. [PMID: 3481318]
17	Stille W, Harder S, Micke S, et al. "Decrease of caffeine elimination in man during co-administration of 4-quinolones." J Antimicrob Chemother 20 (1987): 729-34. [PMID: 3480885]