cimetidine, the elimination half-life and area-under-curve of zolmitriptan and its active metabolites were roughly doubled. Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatine breakdown. Accumulation of creatinine is associated with uremia, but the symptoms of creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups. Like several other medications (e.g. erythromycin), cimetidine interferes with the body's metabolization of sildenafil, causing its strength and duration to increase (therefore also its side effects to be more likely and prominent). Clinically significant drug interactions with the CYP1A2 substrate theophylline, the CYP2C9 substrate tolbutamide, the CYP2D6 substrate desipramine, and the CYP3A4 substrate triazolam have all been demonstrated with cimetidine, and interactions with other substrates of these enzymes are likely as well. Cimetidine has been shown clinically to reduce the clearance of mirtazapine, imipramine, timolol, nebivolol, sparteine, loratadine, nortriptyline, gabapentin, and desipramine in humans. Cimetidine inhibits the renal excretion of metformin and procainamide, resulting in increased circulating levels of these drugs. Interactions of potential clinical importance with cimetidine include warfarin, theophylline, phenytoin, carbamazepine, pethidine and other opioid analgesics, tricyclic antidepressants, lidocaine, terfenadine, amiodarone, flecainide, quinidine, fluorouracil, and benzodiazepines. Cimetidine may decrease the effects of CYP2D6 substrates that are prodrugs, such as codeine, tramadol, and tamoxifen. Cimetidine reduces the absorption of ketoconazole and itraconazole (which require a low pH). Cimetidine has a theoretical but unproven benefit in paracetamol toxicity. This is because N-acetyl-p-benzoquinone imine (NAPQI), a metabolite of paracetamol (acetaminophen) that is responsible for its hepatotoxicity, is formed from it by the cytochrome P450 system (specifically, CYP1A2, CYP2E1, and CYP3A4). Used in cancer metastasis research as a blocker of E-selectin. Numerous other drug interactions. Pharmacology Pharmacodynamics Histamine H2 receptor antagonism The mechanism of action of cimetidine as an antacid is as a histamine H2 receptor antagonist. It has been found to bind to the H2 receptor with a Kd of 42 nM. Cytochrome P450 inhibition Cimetidine is a potent inhibitor of certain cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The drug appears to primarily inhibit CYP1A2, CYP2D6, and CYP3A4, of which it is described as a moderate inhibitor. This is notable since these three CYP isoenzymes are involved in CYP-mediated drug biotransformations; however, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are also involved in the oxidative metabolism of many commonly used drugs. As a result, cimetidine has the