Cimetidine renal elimination

Bendayan R, SuUivan JT, Shaw C, Erecker RC, Sellers EM (1990) Effect of cimetidine and ranitidine on the hepatic and renal elimination of nicotine in humans. Eur J Chn Pharmacol 38(2) 165-169... 

OCT2 to the tubular secretion of cimetidine and famotidine. Furthermore, a great interspecies difference was found in the effect of probenecid, which had no effect on the tubular secretion of famotidine and cimetidine in rats (Fig. 8) (348). Two factors have been proposed for this interspecies difference (1) expression of Octl only in rodent kidney and (2) greater transport activity of famotidine by OAT3 than by Oat3 (120). In monkey, as in the case in human, probenecid had significant effect on the renal elimination of famotidine, but not for cimetidine (152). 

Gisclon LG, Boyd RA, Williams RL, et al. The effect of probenecid on the renal elimination of cimetidine. Clin Pharmacol Ther 1989 45 444-452. 

GUMEPIRIDE H2 RECEPTOR BLOCKERS-CIMETIDINE, RANITIDINE t plasma concentrations of glimepiride and t risk of hypoglycaemic episodes Cimetidine and ranitidine i renal elimination of glimepiride and t intestinal absorption of glimepiride. Cimetidine is also an inhibitor of CYP2D6 and CYP3A4 Consider alternative acid suppression, e.g. proton pump inhibitor (not omeprazole), and monitor more closely... 

Possible mechanisms responsible for this stereoselective renal clearance of pindolol appear to be stereoselective renal metabolism or stereoselective renal secretion (stereoselective binding to plasma proteins was not observed). Recently, Somogyi et al. investigated the effect of coadministration of dmetidine on the renal clearance of the two enantiomers of pindolol (58). Cimetidine significantly reduced the renal clearance of both enantiomers, but reduced the renal clearance of the R enantiomer by a greater extent than the S enantiomer. These data are consistent with the stereoselective renal elimination mechanism for pindolol, with the S enantiomer being preferentially cleared. 

Vincent J, Gardner MJ, Apseloff G, Baris B, Willavize S, Friedman HL. Cimetidine inhibits renal elimination of dofetilide without altering QTc activity onmultiple dosing in healthy subjects. Clin Pharmacol Ther (1998) 63, 210. 

Drugs eliminated via renal mechanisms Coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene, cimetidine, ranitidine, quinidine, and nicotine, potentially could result in altered plasma levels of both agents. 

Histamine H2-receptor antagonists are well absorbed orally, although concurrent antacid therapy may reduce bioavailability by up to 30%. They are widely distributed in the body, crossing the blood-brain barrier and the placenta. Cimetidine, ranitidine and famotidine are extensively metabolised in the liver, and about one-third excreted unchanged in urine, while only one-third of nizatidine is metabolised (Table 11.1). Elimination half-life is increased up to tenfold in renal failure, and doses must be adjusted. 

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated by the kidneys unchanged the remainder is eliminated by the kidneys as inactive metabolites. Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dose must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the QTc and serum electrolytes. A baseline QTC of > 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of < 50 beats/min, and hypokalemia are relative contraindications to its use. 

Pharmacokinetics" the label indicates that "following I.V. or I.M. administration, approximately 75% of the drug is recovered from the urine after 24 hours as the parent compound" (14). Since only one-fourth of the dose is eliminated by nonrenal mechanisms, it can be expected that functionally anephric patients who receive half the usual cimetidine dose, such as the man in the case presented at the beginning of this chapter, will have potentially toxic blood levels that are twice those recommended for patients with normal renal function. 

Interactions of cimetidine and other H -receptor antagonists with the renal secretion of several drugs have been repeatedly described, and comprehensively listed [146]. Thus, cimetidine inhibits renal secretion of procainamide in humans and prolongs its elimination half-life [147,148]. Similar inhibitory effects have been shown on creatinine, ranitidine and many other cationic compounds [149]. 

In humans, serum creatinine is dependent on non renal factors independent of kidney function e.g. muscle mass, nutritional status, infection, volume of distribution. Also, serum creatinine is dependent on renal factors that are independent of function. For example, certain drugs like trimethoprim and cimetidine elevations in serum creatinine by altering the normal elimination pathways of creatinine. In addition, in humans, alterations in serum creatinine may lag several days behind actual changes in GFR. Earher detection of AKI with a kidney specific biomarker may be essential for early and successful treatment of AKI in humans. 

Pharmacokinetics All oral H -receptor antagonists are rapidly absorbed within 1 to 3 hours. Oral bioavailability is lower for ranitidine, cimetidine, and famotidine than for nizatidine. This is because ranitidine, cimetidine, and famotidine are incompletely absorbed and undergo first-pass hepatic metabolism. All of the Hj-receptor antagonists are eliminated via renal filtration and secretion. For this reason, the Hj-receptor antagonist T A may be increased in patients with renal dysfunction. 

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