MOMENT ANALYSIS OF DRUG DISPOSITION IN KIDNEY .5. INVIVO TRANSEPITHELIAL TRANSPORT OF PARA-AMINOHIPPURATE IN RAT-KIDNEY

A new method that can assess the kinetics of in vivo transepithelial transport in rat kidney has been established. The method is based upon a multiple-indicator dilution experiment and the moment analysis theory. After simultaneous bolus injections of p-aminohippurate (PAH) and inulin into the right renal artery, blood samples were taken from the carotid artery and urine was separately collected from right and left ureters. The characteristic response for the first passage of drugs through the right kidney was evaluated by taking blood circulation into consideration. To determine the mean artery-to-vein transit time and the extraction ratio in the kidney, an intravenous injection was also performed as a reference experiment for deconvolution. The urinary excretion curve corresponding to the first passage was obtained as the difference between both kidneys. The mean artery-to-lumen transit time (mean transepithelial transit time, TBAR(cell) was computed by subtracting the mean urinary transit time of inulin from that of secreted PAH. Since transport across the luminal membrane into the lumen from tubular epithelial cells can influence the cellular residence time of drugs, TBAR(cell) and the single-pass mean residence time in epithelial cells (TBAR(cell,sp)) can be thought of describing luminal membrane transport. The value of TBAR(cell) obtained for 0.1 mM PAH was 22 sec and it was prolonged to 61 sec in the presence of probenecid, suggesting an inhibitory effect on transport across the luminal membrane. On the other hand, antiluminal membrane transport into cells from blood is characterized by the volume of distribution in the kidney (Vd(PAH)). Vd(PAH) was remarkably decreased by treatment with probenecid, indicating an inhibitory effect on antiluminal membrane transport. The effects of probenecid on both sides of epithelial cell membrane transport were first demonstrated in vivo. The present method is useful for the analysis of in vivo transepithelial transport including antiluminal and luminal membrane transport for drugs excreted via tubular secretion.