Prolongation and enhancement of serum methotrexate concentrations by probenecid.

Abstract

Various unexpected symptoms and signs were noted in the two groups of patients (including patients who were withdrawn). One patient in the cimetidine group developed pulmonary embolism, one oedema of fingers, one presbyopia, two diarrhoea, and one arterial hypertension. Three patients in the placebo group complained of impotence, headache, and fatigue respectively. Reduced libido was reported by one patient from each group. Laboratory screening tests showed no significantly abnormal findings. Mean blood-pressure values and results of laboratory investigations at the beginning and end of treatment (after completing one year's treatment or at the time of relapse or withdrawal) are shown in table III. During the study one of the departments was moved to another hospital, where different standards were used. This might partly explain the differences in pretrial and post-trial values. The differences between cimetidine and placebo groups, however, were not significant (Mann-Whitney U tests, P 0 05). DiscussionThe possibility that symptomless relapse occurred in some patients and that symptomatic relapse in others was unaccompanied by renewed ulceration cannot be excluded since no patient underwent duodenoscopy. Such possible discrepancies are, however, of limited practical consequence, and we decided that it was more important to choose a design that imitated so far as possible the conditions under which cimetidine may be used in daily clinical practice. Our findings agreed with those of a similar trial conducted by Bodemar and Walan6 in showing that maintenance treatment with cimetidine for one year is highly effective, but we also found that the treatment had no lasting effect. Soon after treatment was completed relapses occurred at about the same rate as in patients whose ulcers had healed spontaneously or during a short course of cimetidine. Wallace et al7 reported severe relapses after cimetidine treatment, but we observed no such incidents in the patients who had received cimetidine for one year or in the patients in the placebo group who had received a short course of cimetidine before entering the maintenance trial. No side effects directly attributable to cimetidine were observed during the trial.Our results suggest that maintenance treatment with cimetidine is a realistic alternative to elective surgery in patients subject to frequent relapses, but several points still need clarification. Firstly, the optimal duration of treatment is not known. Fry8 and Greibe et al9 have shown that duodenal ulcer disease often resolves after a few years, especially in patients diagnosed in general practice, but the average ulcer history of 13 5 years in our patients also shows that prolonged treatment is needed in some cases. It remains to be proved that such treatment is safe and that patients do not acquire tolerance to cimetidine with time, though limited experience in cases of the Zollinger-Ellison syndrome suggests that this is unlikely.10The study was supported by grants 512-6636, 512-8291, and 512-6648 four patie...

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

“…Several drugs, including nonsteroidal anti-inflammatory drugs (Nozaki et al, 2007;Uwai et al, 2004;Maeda et al, 2008), penicillin G (Takeda et al, 2002b), and probenecid (Aherne et al, 1978), are known to inhibit the elimination of MTX. The molecular mechanism underlying these interactions partially relies on the blockade of the renal secretion of antifolate via the basal uptake transporters hOAT3 and hOAT1 (Giacomini et al, 2010).…”

Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family

“…These transporters have been shown to transport a range of relatively large molecules, mostly anionic amphipathic compounds, including bile salts, eicosanoids, and a large number of clinically used steroid hormones and their conjugates, including zidovudine and methotrexate, which are eliminated through the renal route (10). Several drugs, including nonsteroidal anti-inflammatory drugs and probenecid (11), inhibit the elimination of methotrexate and other well-known substrates.…”

Pharmacokinetics of cephradine given intravenously with and without probenecid.

“…Probenecid has since been shown to have this effect with many,l3-lactam antibiotics (Klein & Finland 1963;Mischler, Sugerman, Willard, Brannick & Neiss, 1974). Probenecid also has a similar effect on compounds such as methotrexate (Aherne, Piall, Marks, Mould & White, 1978) and indomethacin (Skeith, Simkin & Healey, 1968). The decrease in the elimination of all these drugs is thought to involve renal tubular inhibition, probenecid competing with the drug for the active transport site(s) (Weiner, Washington & Mudge, 1960).…”