Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI27ZAPSE)
Drug Name			Theophylline		Drug Info		Ofloxacin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Bronchodilators				Antibiotics
Structure

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

Drug Name		Theophylline				Ofloxacin
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 Theophylline caused by Ofloxacin mediated inhibition of CYP450 enzyme

Recommended Action
Management		Interpatient variability of this effect makes it prudent to monitor patients who may not tolerate a small increase in theophylline levels. Levofloxacin, sparfloxacin, and lomefloxacin have been reported to cause minor or no changes in theophylline levels and may be considered as alternatives. Patients should be advised to report any signs of theophylline toxicity including nausea, vomiting, diarrhea, headache, restlessness, insomnia, seizures, or irregular heartbeat to their physicians.

References
1	Ball P "Ciprofloxacin: an overview of adverse experiences." J Antimicrob Chemother 18 (1986): 187-93. [PMID: 3542945]
2	Bowles SK, Popovski Z, Rybak MJ, Beckman HB, Edwards DJ "Effect of norfloxacin on theophylline pharmacokinetics at steady state." Antimicrob Agents Chemother 32 (1988): 510-12. [PMID: 3377462]
3	Covelli HD, Knodel AR, Heppner BT "Predisposing factors to apparent theophylline-induced seizures." Ann Allergy 54 (1985): 411-5. [PMID: 3994071]
4	Davis RL, Kelly HW, Quenzer RW, Standefer J, Steinberg B, Gallegos J "Effect of norfloxacin on theophyllin metabolism." Antimicrob Agents Chemother 33 (1989): 212-4. [PMID: 2719466]
5	Grasela TH, Dreis MW "An evaluation of the quinolone-theophylline interaction using the Food and Drug Administration spontaneous reporting system." Arch Intern Med 152 (1992): 617-21. [PMID: 1312320]
6	Green L, Clark J "Fluoroquinolones and theophylline toxicity: norfloxacin." JAMA 262 (1989): 2383. [PMID: 2795820]
7	Gregoire SL, Grasela TH Jr, Freer JP, Tack KJ, Schentag JJ "Inhibition of theophylline clearance by coadministered ofloxacin without alteraction of theophylline effects." Antimicrob Agents Chemother 31 (1987): 375-8. [PMID: 3472488]
8	Ho G, Tierney MG, Dales RE "Evaluation of the effect of norfloxacin on the pharmacokinetics of theophylline." Clin Pharmacol Ther 44 (1988): 35-8. [PMID: 3391003]
9	Hooper DC, Wolfson JS "The fluoroquinolones: pharmacology, clinical uses, and toxicities in humans." Antimicrob Agents Chemother 28 (1985): 716-21. [PMID: 2936302]
10	Product Information. Cinobac (cinoxacin). Oclassen Pharmaceuticals Inc, San Rafael, CA.
11	Raoof S, Wollschlager C, Khan FA "Ciprofloxacin increases serum levels of theophylline." Am J Med 82 (1987): 115-8. [PMID: 3578320]
12	Sano M, Yamamoto I, Ueda J, Yoskikawa E, Yamashina H, Goto M "Comparative pharmacokinetics of theophylline following two fluoroquinolones co-administration." Eur J Clin Pharmacol 32 (1987): 431-2. [PMID: 3475207]
13	Segev S. Rehavi M, Rubinstein E "Quinolones, theophylline, and diclofenac interactions with the gamma-aminobutyric acid receptor." Antimicrob Agents Chemother 32 (1988): 1624-6. [PMID: 2855295]
14	Upton RA "Pharmacokinetic interactions between theophylline and other medication (Part I)." Clin Pharmacokinet 20 (1991): 66-80. [PMID: 1674242]
15	Wijnands WJ, Vree TB "Interaction between the fluoroquinolones and the bronchodilator theophylline." J Antimicrob Chemother 22 (1988): 109-14. [PMID: 3053575]
16	Wijnands WJ, Vree TB, Baars AM, van Herwaarden CL "Steady-state kinetics of the quinolone derivatives ofloxacin, enoxacin, ciprofloxacin and pefloxacin during maintneance treatment with theophylline." Drugs 34 (1987): 159-69. [PMID: 3481317]