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Probenecid interferes with renal oxidative metabolism: A potential pitfall in its use as an inhibitor of drug transport
Author(s) -
Masereeuw Rosalinde,
Van Pelt Ard P,
Van Os Sandra H G,
Willems Peter H G M,
Smits Paul,
Russel Frans G M
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703541
Subject(s) - probenecid , oxidative metabolism , oxidative phosphorylation , pharmacology , drug , drug metabolism , chemistry , metabolism , liver metabolism , medicine , biochemistry
The anionic drug probenecid has been traditionally used as an inhibitor of renal organic anion transport. More recently the drug was found to inhibit organic cation transport as well, and it is used to retain intracellularly loaded fluorophores. In these investigations it is implicitly assumed that probenecid performs its activity through competition for transport. Here we studied the possibility that probenecid provokes its effect through inhibition of cellular oxidative metabolism. Oxygen consumption was measured in isolated rat kidney cortex mitochondria. At concentrations of 1 m M or higher, probenecid increased the resting state (state 4) and decreased the ADP‐stimulated respiration (state 3). A complete loss in respiratory control was observed at 10 m M probenecid. After incubating isolated rat kidney proximal tubular cells (PTC) for 30 min with probenecid a concentration‐dependent reduction in ATP content was observed, which was significant at concentrations of 1 m M and higher. Using digital image fluorescence microscopy the membrane potential in PTC was measured with bisoxonol. The mitochondrial effects of probenecid were paralleled by a depolarization of the plasma membrane, immediately after drug addition. All events are likely to be a result of membrane disordering due to the lipophilic character of probenecid, and may explain, at least in part, the various inhibitory effects found for the drug. We recommend to be cautious with applying probenecid in cellular research.British Journal of Pharmacology (2000) 131 , 57–62; doi: 10.1038/sj.bjp.0703541