Inhibition of amino acid transport by nonsteroidal anti-inflammatory drugs: a model for predicting relative therapeutic potency

GF Seng and BM Bayer

Indomethacin has been shown to inhibit selectively the rate of alpha- (methylamino)-isobutyric acid (MeAIB) uptake by the "A" transport system in several cell types. This study was undertaken to determine if this activity was shared by other nonsteroidal anti-inflammatory drugs (NSAID), if the inhibition of MeAIB transport was unique to drugs with anti-inflammatory activity and finally if it could be correlated with their in vivo potency in humans and in animal test systems. Utilizing BRLT rat hepatocyte cultures (hepatocytes cloned from Buffalo rats); it was found that all of the acidic NSAID tested inhibited MeAIB uptake in a dose-dependent manner with IC50 values in the low to midmicromolar range. The amount of inhibition was dependent on cell density, time of incubation with drug, the media pH and its concentration of protein and amino acids. The order of potency of the acidic NSAID in inhibiting MeAIB uptake was found to be correlated closely with their potency in the inhibition of prostaglandin synthesis in vitro, the suppression of induced inflammatory reactions in rats and the maximum recommended daily doses in humans. Pharmacologically inactive metabolites of several NSAID had little or no effect on MeAIB transport at concentrations up to 10 times greater than active parent compounds. Other compounds tested, including glucocorticoids, were found to have little effect on the rate of MeAIB uptake. These studies indicate that the inhibition of MeAIB uptake in BRLT cells may represent a reliable and rapid screen for predicting the therapeutic potency of newly developed NSAID.

Volume 237, Issue 2, pp. 496-503, 05/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics