Assessment of the Potential for Veverimer Drug-Drug Interactions.

Veverimer is a polymer being developed as a potential treatment of metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral, or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiologic concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. SIGNIFICANCE STATEMENT: Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.

Microbial biotransformation of furosemide for environmental risk assessment: identification of metabolites and toxicological evaluation.

Some widely prescribed drugs are sparsely metabolized and end up in the environment. They can thus be a focal point of ecotoxicity, either themselves or their environmental transformation products. In this context, we present a study concerning furosemide, a diuretic, which is mainly excreted unchanged. We investigated its biotransformation by two environmental fungi, Aspergillus candidus and Cunninghamella echinulata. The assessment of its ecotoxicity and that of its metabolites was performed using the Microtox test (ISO 11348-3) with Vibrio fischeri marine bacteria. Three metabolites were identified by means of HPLC-MS and 1H/13C NMR analysis: saluamine, a known pyridinium derivative and a hydroxy-ketone product, the latter having not been previously described. This hydroxy-ketone metabolite was obtained with C. echinulata and was further slowly transformed into saluamine. The pyridinium derivative was obtained in low amount with both strains. Metabolites, excepting saluamine, exhibited higher toxicity than furosemide, being the pyridinium structure the one with the most elevated toxic levels (EC50 = 34.40 ± 6.84 mg L-1). These results demonstrate that biotic environmental transformation products may present a higher environmental risk than the starting drug, hence highlighting the importance of boosting toxicological risk assessment related to the impact of pharmaceutical waste.

A coupled Bio-EF process for mineralization of the pharmaceuticals furosemide and ranitidine: Feasibility assessment.

A coupled Bio-EF treatment has been applied as a reliable process for the degradation of the pharmaceuticals furosemide (FRSM) and ranitidine (RNTD) in aqueous medium, in order to reduce the high energy consumption related to electrochemical technology. In the first stage of this study, electrochemical degradation of the drugs was assessed by the electro-Fenton process (EF) using a BDD/carbon-felt cell. Biodegradability of the drugs solutions was enhanced reaching BOD5/COD ratios close to the biodegradability threshold of 0.4, evidencing the formation of bio-compatible by-products (mainly short-chain carboxylic acids) which are suitable for biological post-treatment. Moreover, toxicity evaluation by the Microtox(®) method revealed that EF pre-treatment was able of detoxifying both, FRSM and RNTD solutions, constituting another indicator of biodegradability of EF treated solutions. In the second stage, electrolyzed solutions were treated by means of an aerobic biological process. A significant part of the short-chain carboxylic acids formed during the electrochemical phase was satisfactorily removed by the used selected microorganisms. The results obtained demonstrate the efficiency and feasibility of the integrated Bio-EF process.