Studies on the pharmacology of the inward transport of L‐DOPA in rat renal tubules

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Abstract
The accumulation of L‐DOPA in suspensions of renal tubules obtained from male Wistar rats occurred through non‐saturable and saturable mechanisms. The kinetics of the saturable component of L‐DOPA uptake in renal tubules was as follows: Vmax = 46.3 ± 2.8 nmol mg−1 protein h−1 and Km = 114.4 (95% confidence limits; 83.8, 156.2) μm (n = 5). The diffusion constant (in nmol−1) of the non‐saturable component for the accumulation of L‐DOPA was 1.3 (1.1, 1.6; n = 8). The effect of 2, 4‐dinitrophenol was a marked reduction in the tubular uptake of L‐DOPA, with an IC50 value of 12.1 (4.0, 36.9) μm. Cocaine produced a slight (P = 0.08) decrease (22% reduction at 50 μm) in the tubular uptake of L‐DOPA. Corticosterone produced a considerable inhibitory effect on the uptake of L‐DOPA with an IC50 value of 11.0 (3.6, 33.5) μm. The maximal inhibitory effect of probenecid was a 24% decrease in the uptake of L‐DOPA; however, the more selective organic anion transport inhibitor 4, 4′‐diisothiocyantostilbene‐2, 2′‐disulphonic acid (DIDS) was, found not to affect the tubular uptake of L‐DOPA. The organic cation transport inhibitor, cyanine 863, was found to produce a marked decrease in the uptake of L‐DOPA (IC50 = 2.02 [1.07, 3.79]). The cyanine derivatives 1, 1′‐diethyl‐2, 2′‐cyanine (decynium 22) and 1, 1′‐diethyl‐2, 4′‐cyanine (decynium 24) also potently inhibited L‐DOPA uptake with IC50 values (in μm) of 0.63 (0.39, 1.01) and 0.10 (0.08, 0.13), respectively, both compounds were found to be more potent than cyanine 863. The inhibitory effect of decynium 24 (0.2 μm) on the tubular uptake of L‐DOPA was dependent on the pH of the incubation medium; at pH = 6.5 the accumulation of L‐DOPA was reduced up to 37 ± 2% of control values, whereas at pH = 7.4 and pH = 8.2 the accumulation of L‐DOPA was reduced by 56 ± 1% and 60 ± 6%, respectively. Cyanine 863 (2 μm), decynium 22 (1 μm) and decynium 24 (0.2 μm) were found to decrease the Vmax values for the saturable component of L‐DOPA uptake without changes in Km values. It is concluded that the tubular uptake of L‐DOPA might be promoted through a mechanism which is dependent on the activity of the organic cation transport system.