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Renal, biliary

Source: Facts and Comparisons 4.0, Wolters Kluwer Health, Amsterdam, Netherlands, 2009.

Source: Facts and Comparisons 4.0, Wolters Kluwer Health, Amsterdam, Netherlands, 2009.

famotidine have lower oral bioavailabilities than nizatidine as a result of greater first-pass metabolism. Based on their common structural features, most of these agents are metabolized by s- and n-oxidation. The imidazole ring of cimeti-dine serves as an addition site for oxidative metabolism, as do the n,n-dimethyl functionalities of nizatidine and ranitidine. All of these metabolites are presumed to be inactive, or at least less active than the parent drugs. Also, a significant proportion of the dose of each of the H2-antagonists is excreted renally in unmetabolized form. The half-lives of these agents range from 1 to 4 hours, with nizatidine having the shortest half-life.66 The properties of the individual H2-antagonists that are in clinical use in the United States are described and compared in the monographs that follow.

Cimetidine, USP. Cimetidine, n^-cyano-n-methyl-n7-[2-[[5-methylimidazol-4-yl)methyl]thio]ethyl]guanidine (Tagamet), is a colorless crystalline solid that is slightly soluble in water (1.14% at 37°C). The solubility is greatly increased by the addition of dilute acid to protonate the im-idazole ring (apparent pKa of 6.8). At pH 7, aqueous solutions are stable for at least 7 days. Cimetidine is a relatively hydrophilic molecule with an octanol/water partition coefficient of 2.5.

Cimetidine inhibits the hepatic metabolism of drugs bio-transformed by various CYP isozymes, delaying elimination and increasing serum levels of these drugs. Thus, concomitant therapy with cimetidine and drugs metabolized by hepatic cytochrome isozymes or in patients with renal or hepatic impairment may require dosage adjustment. This is particulary true for drugs with relatively low therapeutic indices including warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, benzodiazepines, certain tricyclic antidepressants, lidocaine, theophylline, and metronidazole.66 Additionally, cimetidine administration may increase gastric pH and decrease the absorption of drugs such as the azole antifungals (e.g., ketoconazole), which require an acidic environment for dissolution.66 If concurrent azole therapy is required, it is best to administer it at least 2 hours before cimetidine administration. Cimetidine has a weak an-tiandrogenic effect, and it may cause gynecomastia in patients treated for 1 month or more.

Cimetidine exhibits relatively good bioavailability (60%-70%) and a plasma half-life of about 2 hours, which is increased in renal and hepatic impairment and in the elderly. Approximately 30% to 40% of a cimetidine dose is metabolized (s-oxidation, 5-CH3 hydroxylation), and the parent drug and metabolites are eliminated primarily by renal excretion.66 Antacids interfer with cimetidine absorption and should be administered at least 1 hour before or after a cimetidine dose.

Dosage forms: Tablet (200, 300, 400, 800 mg), liquid

(300 mg/5 mL), injection (150/mL and 6 mg/mL) Usual adult oral dose:

• Benign gastric ulcer: 800 or 300 mg 4 times a day

• Duodenal ulcer: 800 or 300 mg 4 times a day (with meals and at bedtime); maintenance dose, 400 mg 4 times a day

• Gastroesophageal reflux disease, erosive: 1,600 mg daily in divided doses (800 mg twice daily or 400 mg 4 times per day) for 12 weeks

• Heartburn relief or prevention (OTC): 200 mg with water as symptoms occur or right before or any time up to 30 minutes before eating food or drinking; maximum dosage, 400 mg/day

• Pathological hypersecretory conditions: 300 mg 4 times per day with meals and at bedtime; maximum dosage, 2,400 mg/day

• Usual pediatric dose: Oral, 20 to 40 mg (base) per kilogram of body weight 4 times a day with meals and at bedtime

Famotidine, USP. Famotidine, W-(aminosulfonyl)-3-[[[2[(diamnomethylene)amino]-4-thiazolyl]methyl] thio]propanimidamide (Pepcid), is a white to pale-yellow crystalline compound that is very slightly soluble in water and practically insoluble in ethanol. It is a thiazole bioisotere of cimetidine that contains a guanidine substituent that may mimic the imizadole of cimetidine.

Famotidine is a competitive inhibitor of histamine H2-receptors with a potency significantly greater than cimeti-dine. It inhibits basal and nocturnal gastric secretion as well as secretion stimulated by food and pentagastrin. Its current labeling indications are for the short-term treatment of duodenal and benign gastric ulcers, GERD, pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome), and heartburn (OTC only).66

No cases of gynecomastia, increased prolactin levels, or impotence have been reported, even at the higher dosage levels used in patients with pathological hypersecretory conditions. Studies with famotidine in humans, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by cytochrome isozymes. No significant interactions have been detected with warfarin, theophylline, phenytoin, diazepam, aminopy-rine, and antipyrine.

Famotidine is incompletely absorbed (37%-45% bioavailability).66 The drug is eliminated by renal (65%-70%) and metabolic (30%-35%) routes. Famotidine sulfoxide is the only metabolite identified in humans. The effects of food or antacid on the bioavailability of famotidine are not clinically significant.

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