Cimetidine selective toxicity

Isosteric replacement of the thiourea moiety with the cyanoguanidine moiety gave cimetidine (39), a potent H2-receptor antagonist that lacks the toxicity of 38. Cimet-idine is a widely used anti-ulcer medication because of its effectiveness in treating ulcers and relative safety. It is noteworthy that in this example, this isosteric modification selectively reduced toxicity without affecting pharmacological activity. 

In contrast, decreases in theophylline metabolism by selective inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, or by selective and potent inhibitors of CYP3A4, such as the macrolide antibiotics, have resulted in serious theophylline toxicity (22). It is postulated that taken over time, the macrolide antibiotics act as mechanism-based inhibitors of CYP isoforms other than just CYP3A4. Some nonselective inhibitors of P450s, such as cimetidine, some p-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. 

CIMETIDINE VINCA ALKALOIDS T adverse effects of vinblastine and vincristine Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine Monitor FBCs and watch for early features of toxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation, ileus). Consider selecting an alternative drug... 

Several other reports have demonstrated that coumarin in combination with cimetidine can produce objective antitumor responses in some patients with advanced melanoma [171,172]. There are reports that review the clinical development of coumarin, with or without cimetidine, with special reference to renal cell carcinoma (RCC) [173,174]. While objective tumor regressions were observed in renal carcinoma, no symptomatic or organ dysfunction toxicity was observed in any of the trials [175]. Some results suggest osthole as a selective antiproliferative agent in vascular smooth muscle cells. The antiproliferative effect occurs at the early G1 phase of the cell cycle and is due to the increase in cyclic AMP and cyclic GMP contents [176]. 

I. Pharmacology. Cimetidine, ranitidine, famotidine, and nizatidine are selective competitive inhibitors of histamine on Hj receptors. These receptors modulate smooth muscle, vascular tone, and gastric secretions and may be involved in clinical effects associated with anaphylactic and anaphylactoid reactions, as well as ingestion of histamine or histamine-like substances (eg, scombroid fish poisoning). Cimetidine, as an inhibitor of cytochrome P-450 enzymes, has been proposed or studied in animals as an agent to block the production of toxic intermediate metabolites (eg, acetaminophen, carbon tetrachloride, halothane. 

Mitchell MC, Schenker S, Spe KV. Selective inhibition of acetaminophen oxidaticn and toxicity by cimetidine and otiier histamine H2-receptor antagonists in vivo and in vitro in rat andinman. JC/m/wv 5/(1984) 73,383-91. 

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