The effect of probenecid on the renal elimination of cimetidine

Abstract

It is generally assumed that the systems involved in the transport of organic cations and organic anions in the renal proximal tubule are substrate selective (i.e., organic anions do not inhibit organic cation transport and vice versa). However, recent data obtained in vitro have suggested that the organic anion probenecid inhibits the renal transport of the organic cation cimetidine. We addressed the question of whether this interaction is biologically relevant in human beings. The study involved a two-treatment, randomized crossover design. Six healthy male subjects were given an intravenous infusion of 300 mg cimetidine alone as one treatment and, as the other treatment, received multiple oral doses of probenecid before receiving the cimetidine infusion. The renal clearance of cimetidine and inulin was determined in each period. There were no significant differences between treatments in cimetidine plasma concentrations, apparent volume of distribution, systemic clearance, half-life, amount of drug excreted unchanged in the urine, or nonrenal clearance. Probenecid significantly decreased the renal clearance of cimetidine by decreasing both the filtration clearance and the net secretory clearance. These effects were most evident in the first 1/2 to 1 hour after cimetidine administration, when probenecid levels in plasma and renal tissue would have been the highest. Because there was no effect of probenecid on cimetidine plasma concentrations, this interaction is not clinically relevant to the therapeutic use of these two compounds. However, the study demonstrates that renal interactions between organic cations and organic anions can occur in human beings. The mechanism of this interaction and the implications to other drug combinations are being explored.

No effect of probenecid on the renal and biliary clearances of digoxin in man.

“…This finding is difficult to explain, although two mechanisms are possible-a reduction of the glomerular filtration rate (GFR) by probenecid or an inhibition of the secretory component of creatinine elimination. It has been reported (Gisclon et al, 1989) that probenecid decreases GFR (inulin clearance) in man by 29%. This decrease in GFR is comparable with the extent of impairment of creatinine clearance found in our study, as well as with the results reported in two other studies in humans where probenecid reduced inulin clearance by 22% and 27% (Odlind et al, 1983a,b).…”

“…Probenecid is reported to have a modest inhibitory effect in vitro on the uptake of another glycoside, ouabain, in rat liver slices (Erttmann & Damm, 1974) and in rat isolated hepatocytes (Eaton & Klaassen, 1978) as well as being able to lower the renal clearance of cimetidine in healthy volunteers (Gisclon et al, 1989). Hence, the question arises whether an anion like probenecid may affect secretion and thus the kinetics of digoxin in man.…”

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

“…Organic anion transporters (OAT) and organic cation transporters (OCT) are involved in active renal secretion of numerous drug molecules [5] and have been found also at various other sites in the body. Probenecid has been reported to interact with both [21,22].…”

“…Blood samples were taken before the start of the ciprofloxacin infusion, 10 and 20 min after the start of infusion, at the end of infusion, and 5, 10, 20, 30, 45, 60 and 90 min and 2, 3,4,5,6,8,10,12,16,24,30,36 and 48 h after the end of the infusion. The samples were centrifuged immediately.…”

“…At physiological pH values, ciprofloxacin exists primarily as a zwitterion.Therefore it is likely to interact with organic anion as well as organic cation transporters in the renal tubular cells [2]. Probenecid has been reported to inhibit active transport of both anionic and cationic drug molecules at various sites in the body [3][4][5]. Furthermore, it is well known to decrease the renal secretion of numerous quinolones such as gatifloxacin [6],levofloxacin [7,8],norfloxacin [9],fleroxacin [10] and enoxacin [11].…”