Details of Drug-Drug Interaction
| Drug General Information (ID: DDIDMAGJU3) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Drug Name | Zileuton | Drug Info | Alosetron | Drug Info | |||||
| Drug Type | Small molecule | Small molecule | |||||||
| Therapeutic Class | Antiinflammatory Agents | Gastrointestinal Agents | |||||||
| Structure | |||||||||
| Mechanism of Zileuton-Alosetron Interaction (Severity Level: Moderate) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph | |||||||||
 |
|||||||||
| Drug Name | Zileuton | Alosetron | |||||||
| Mechanism | CYP450 1A2 inhibitor | CYP450 1A2 substrate | |||||||
| 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 |
|
||||||||
| Recommended Action | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Management | Because alosetron is associated with potentially serious and life-threatening, dose-related gastrointestinal adverse effects, concomitant use with CYP450 1A2 inhibitors should generally be avoided if possible (use with fluvoxamine is specifically contraindicated). If coadministration is required, it may be appropriate to initially prescribe a lower dosage of alosetron (e.g., 1 mg once a day). However, the product labeling does not offer recommendations for a dosage adjustment. Patients should be advised to immediately discontinue alosetron and notify their physician if they experience constipation or signs and symptoms of ischemic colitis such as rectal bleeding, bloody diarrhea, and new or worsening abdominal pain. Alosetron should not be resumed if ischemic colitis is diagnosed. Ischemic colitis and other serious complications such as obstruction, perforation, impaction, and toxic megacolon have resulted in hospitalization, blood transfusion, surgery, and death. | ||||||||
| References | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Product Information. Lotronex (alosetron). Glaxo Wellcome, Research Triangle Park, NC. | ||||||||||||||||||