Renal clearance cimetidine

In vitro stndies have shown that there are distinct transport systems for both baso-lateral and apical uptake of nicotine (Takami et al. 1998). Nicotine has been shown to be actively transported by kidney cells, most likely by the organic ion transporter OCT2 (Zevin et al. 1998 Urakami et al. 1998). Cimetidine decreases renal clearance of nicotine by 47% in nonsmoking volunteers (Bendayan et al. 1990). This is consistent with the inhibition of basolateral uptake by cimetidine detected in vitro. Mecamylamine reduces renal clearance of nicotine in smokers dosed with intra-venons nicotine when urine is alkalinized, but not when nrine is acidified (Zevin et al. 2000). 

Renal clearance of creatinine, and of cationic drugs which undergo active proximal tubular excretion, is reduced by cimetidine and to a lesser extent by ranitidine. 

Boom SP, Meyer I, Wouterse AC, et al. A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog. Biopharm Drug Dispos 1998 19 199-208. 

Drayer DE, Romankiewicz J, Lorenzo B, Reidenberg MM. Age and renal clearance of cimetidine. Clin Pharmacol Ther 1982 31 45-60. 

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. 

A. A. Somogyi, F. Bochner, and B. C. SaUustio, Stereoselective inhibition of pindolol renal clearance by cimetidine in humans, Clin. Pharmacd. Ther., 5 379-387 (1992). 

The many drug interactions described with cimetidine are largely attributable to inhibition of CYP isozymes or renal clearance of other drugs. Cimetidine also reduces hepatic blood flow and so can, for example, reduce the clearance of lidocaine. In the kidneys cimetidine interferes with the tubular excretion of procainamide and quinidine. Both effects are small, and the long list of drugs for which interference is demonstrable (Table 1) is out of all proportion to the number for which interference is of chnical significance. 

In a randomized, placebo-controlled study of the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide 500 micrograms in 20 healthy men, ranitidine 150 mg bd did not affect the pharmacokinetics or pharmacodynamics of dofetilide, but there was a dose-dependent increase in exposure to dofetilide with cimetidine (61). With cimetidine 100 and 400 mg bd the AUC of dofetilide increased by 11 and 48%, the maximum plasma dofetilide concentration increased by 11 and 29%, renal clearance fell by 13 and 33%, and non-renal clearance by 5 and 21% dofetilide-induced prolongation of the QT interval was increased by 22 and 33%. The authors suggested that cimetidine inhibited renal tubular dofetilide secretion,... 

The clinical significance of the reduced renal clearance of oxaprozin when it is given concomitantly with cimetidine is not clear (SEDA-12, 87). 

A chronic-dosing pharmacokinetic study has been carried out in six healthy subjects to examine the potential for cimetidine to reduce the renal and hepatic clearance of triamterene.66 Blood and urine samples were collected frequently for 24 hours after dosing with triamterene alone (100 mg/day) for 4 days and concomitant cimetidine (400 mg twice daily) for an additional 4 days. Cimetidine reduced the clearance of triamterene by hydroxylation by 32%, renal clearance of triamterene by 28%, with no change in its protein binding. The renal clearance of the active sulfate conjugate was not altered by cimetidine. There was a reduced recovery of triamterene and its metabolites in urine after cimetidine,... 

To assess selectivity in the inducing and inhibiting effects of environmental factors (for example, dmg treatment) on the activity of the different P-450 enzymes. In one of such smdies, nifedipine, sparteine, mephenytoin and antipyrine were administered simultaneously to 15 healthy subjects, including four poor metabohzers of sparteine and four poor metabolizers of mephenytoin [6], They received the cocktail on three different occasions without pretreatment, after pentobarbital pretreatment and together with cimetidine. Concentrations of nifedipine, its pyridine metabolite, and of sparteine and its dehydro metabolite were measured in the plasma nifedipine metabohtes, sparteine, dehydrosparteine, 4-hydroxymephenytoin, antipyrine and its three major metabohtes were all measured in urine. The kinetic parameters obtained clearly indicated that nifedipine metabolism is very sensitive to pentobarbital induction (Fig. 4), whereas antipyrine metabolism is sensitive only to a moderate degree and sparteine metabolism is unaffected. Cimetidine inhibited the metabohc clearance of all three compounds to a similar extent and also inhibited renal clearance of sparteine, most likely at the level of tubular secretion. Urinary excretion of 4-... 

Cimetidine not only reduces the metabolism of beta-blockers such as propranolol, it is also known to act as an inhibitor of tubular secretion of a number of organic cations. Therefore it is not surprising to see that the renal clearance of pindolol is substantially and stereoselectively reduced by coadministration of this drug [59]. The administration of 400 mg cimetidine twice a day for 2 days before and 2 days after pindolol administration resulted in 26% and 34% reductions in the renal clearances of S(—)- and R(-t-)-pindolol, respectively. Therefore the plasma concentrations of the R(-l-) enantiomer increased more drastically (47%) than those of the S(—) enantiomer (38%) in the presence of cimetidine [59]. Because renal clearance accounts for only 50% of pindolol elimination, the significant increases in the plasma concentrations of pindolol enantiomers as a result of cimetidine coadministration cannot be explained from the inhibition of its renal clearance only. Apparently, cimetidine also reduces the metabolism of pindolol. 

After faking cimetidine 1 g daily for a week, the AUC of a single 200-mg dose of flecainide was increased by 28% in 8 healthy subjects. The fraction of flecainide excrefed unchanged in the urine was increased by 20%, but the total renal clearance was not altered. In another study in 11 patients, cimetidine 1 g daily for 5 days almost doubled the plasma levels of flecainide 200 mg daily measured 2 hours after the morning dose. ... 

Hardy BG, Schentag JJ. Lack of effect of cimetidine on the metabolism of quinidine effect on renal clearance. Inij Clin Pharmacol Ther Toxicol (1988) 26, 388-91. 

The plasma levels of a 400-mg intravenous dose of enoxacin were higher when cimetidine 300 mg four times daily was given concurrently. Renal clearance and systemic clearance were reduced by 26% and 20%, respectively, and the elimination half-life was increased by 30%. ... 

Cimetidine decreased the total clearance of fleroxacin by about 25%, without much effect on renal clearance, and increased its elimination half-life by 32%. ... 

Cimetidine 800 mg daily was found to reduce the renal clearance of metformin in 7 healthy subjects by 27% and increase the AUC by 50%. A 59-year-old woman with type 2 diabetes taking long-term metformin 500 mg three times daily developed severe metabolic acidosis with cardiovascular collapse and acute renal failure. Three months previously she had started orlistat 120 mg three times daily, which caused chronic diarrhoea. During the 4 days before hospital admission, she was prescribed cimetidine 400 mg twice daily for her abdominal pain. The metformin-assoeiated lactic acidosis was considered to have been precipitated by the orlistat , (p.498) and cimetidine. ... 

A brief report notes that cimetidine decreased the renal clearance of gabapentin by 12%, which was not expected to be clinically important. No study details were given. ... 

Cimetidine 400 mg twice daily for 6 days did not cause any changes in the plasma pharmacokinetics of a single 120-mg dose of fexofenadine in 12 healthy subjects. However, the renal clearance of fexofenadine was decreased by 39%. ... 

Cimetidine and ranitidine probably do not have a clinically relevant effect on the renal clearance of cisplatin. 

In a study, 12 healthy subjects were given cimetidine 400 mg twice daily for 8 days with a single 500-mg dose of famciclovir, a prodrug for penci-clovir, on the last day. The AUC of penciclovir was increased by about 18% by cimetidine, but there was no change in renal clearance. ... 

Twelve healthy subjects were given a 1-g dose of valaciclovir alone or with cimetidine 800 mg, taken 10 hours and 1 hour before. The AUC0.3 for the prodrug valaciclovir was increased by 73% by cimetidine, and the AUCo.24 for the active metabolite of valaciclovir, aciclovir, was increased by 27%. The renal clearance of aciclovir was reduced by 22%, although the total urinary recovery of aciclovir was unchanged. ... 

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