Drug inhibition of penicillin tubular secretion: concordance between in vitro and clinical findings.

Using the rabbit kidney slice model of active tubular secretion, I studied the active accumulation of penicillin (PEN) in the absence and presence of competing drugs to evaluate the feasibility of using in vitro uptake to predict in vivo secretion. Active accumulation of PEN by these slices was saturable at high PEN concentrations and was inhibited by incubation conditions which decreased ATP production. PEN uptake in the presence of 1 mM concentrations of mannitol, tolazoline and tetraethylammonium was unchanged. However, PEN uptake in the presence of eight weak organic acid drugs (probenecid, phenylbutazone, sulfinpyrazone, salicylate, sulfamethizole, chlorothiazide, sulfamethoxypyridazine and indomethacin) was inhibited significantly. This inhibition appeared to be competitive in nature and the inhibitor-transport carrier protein dissociation constant (Ki) for each inhibitory drug was calculated (range, 0.38-74.8 X 10(-5) M). When these values for Ki obtained with PEN were compared to values obtained with methotrexate and p- aminohippurate, the values of Ki were similar, implying the presence of a similar transport carrier protein for PEN, methotrexate and p-aminohippurate. The effects of these eight drugs upon PEN clearance in vivo were extrapolated from the medical literature. The relative inhibitory strengths of these drugs based upon in vitro findings (drug plasma concentration/Ki ratios) and clinical findings (inhibition of PEN clearance) were concordant. This in vitro model for assessing inhibition of renal tubular secretion may be of general utility in predicting clinically important drug interactions between weak organic acid drugs.(ABSTRACT TRUNCATED AT 250 WORDS)