Transport of methotrexate in cortical slices of monkey kidney: effect of organic anions and vincristine.
Thin cortical slices of cynamolgus and rhesus monkey kidney were used to study the renal transport of methotrexate (MTX). In experiments with renal cortical slices, MTX uptake at 25 degrees C was linear over the initial 30 min and was temperature-dependent. The Km was 0.094 mM for MTX uptake at 25 degrees C and Vmax was 0.098 mumol/g of tissue/30 min. In the presence of either 1 mM 2,4-dinitrophenol, p-aminohippurate or acetylsalicylate, MTX uptake was competitively inhibited. 2,4-Dinitrophenol had the greatest and acetylsalicylate had the least inhibitory effect. Folinic acid, folic acid and ouabain produced little or no effect on MTX uptake. MTX efflux from preloaded slices (preincubated with 0.5 mM MTX for 45 min) was a first-order process with T 1/2 of 7.13 +/- 0.86 min. In the presence of vincristine or p-aminohippurate the half-lives for MTX were 15.25 +/- 0.91 and 4.59 +/- 0.47 min, respectively. Thus vincristine, an organic base, was found to augment MTX uptake, due to a reduction in the rate of efflux of MTX from the cortical tissues, whereas p-aminohippurate, an organic acid, was found to decrease MTX intracellular concentration by blocking influx and stimulating efflux. It was concluded that the renal transport of MTX in monkey kidney is mediated predominantly by an organic anion secretory process and that there is probably little or no reabsorptive transport.
D019297:2,4-Dinitrophenol; D000618:Aminohippuric Acids / Q000494:pharmacology*; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D004140:Dinitrophenols / Q000494:pharmacology; D005260:Female; D005492:Folic Acid / Q000494:pharmacology; D007672:Kidney Cortex / Q000378:metabolism*; D007700:Kinetics; D002955:Leucovorin / Q000494:pharmacology; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008727:Methotrexate / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology*; D010130:p-Aminohippuric Acid / Q000494:pharmacology*
D000618:Aminohippuric Acids; D004140:Dinitrophenols; D010042:Ouabain; D014750:Vincristine; D005492:Folic Acid; D019297:2,4-Dinitrophenol; D002955:Leucovorin; D001241:Aspirin; D010130:p-Aminohippuric Acid; D008727:Methotrexate