Uptake of probenecid by rat liver slices

The uptake of 14C-probenecid by rat liver has been studied by standard tissue-slice methods. No metabolites of this transport inhibitor accumulated in the slices, but the.parent drug and a single metabolite appeared in the incubation media. The metabolite was identified by GLC-MS procedures as the glucuronide of side-chain hydroxylated probenecid. Maximum slice/medium (S/M) ratios of 2 to 3 were obtained at 20–60 min. Metabolic inhibitors ( N-ethylmaleimide, iodoacetate, and DNP, but not NaCN) decreased the S/M ratios after 1hr incubation. Of 7 anionic compounds tested as potential inhibitors of probenecid uptake, only iopanoic acid (telepaque) and sulfo-bromophthalein (BSP) produced significant depression of S/M ratios in 20 min incubated slices. Neither of the three cationic compounds tested depressed the S/M ratios of any time period studied (20, 60, or 120 min). All of the potential inhibitors were also tested for their effects on probenecid binding to rat liver homogenates. Iopanoic acid and DNP dramatically decreased probenecid binding, while enhanced binding to homogenates was observed in the presence of tyropanoate, procainamide ethobromide, or chloro-quanide triazine. On the basis that various inhibitors could decrease binding and/or transport, the conclusion was reached that the liver slice uptake of probenecid occurs both by nonspecific binding and by organic acid transport mechanisms.