Differential effects of histamine H2 receptor antagonists on amantadine uptake in the rat renal cortical slice, isolated proximal tubule and distal tubule
Wong, L.T.; Smyth, D.D.; Sitar, D.S.
Journal of Pharmacology and Experimental Therapeutics 258(1): 320-324
1991
ISSN/ISBN: 0022-3565 PMID: 2072304 Document Number: 384986
The interaction between amantadine and two histamine receptor antagonists was examined in the rat kidney. Amantadine (10 microM, 30 sec) was actively accumulated by cortical slices (slice/medium ratio = 0.4 +/- 0.3 [3.3 +/- 0.3 at 4 min], mean +/- S.E.M.), isolated proximal tubules (tubule/medium ratio = 35 +/- 1) and distal tubules (tubule/medium ratio = 19 +/- 2). In cortical slices, low cimetidine concentrations facilitated amantadine accumulation, whereas higher concentrations produced inhibition. Uptake in proximal tubules was enhanced by cimetidine and reached a maximum at approximately 100 microM. Cimetidine (20 microM) decreased the apparent Km (88 +/- 5 to 55 +/- 3 microM, P less than .005) without altering Vmax (6.8 +/- 0.5 to 5.8 +/- 0.6 nmol/mg/min). Conversely, cimetidine did not enhance uptake in distal tubules but elicited competitive inhibition at concentrations greater than 1 mM. Although this may partially delineate the differences observed between the cortical slice and proximal tubule data, such a discrepancy may also implicate additional sites of interaction in other segments of the cortical nephron and/or cimetidine inhibition of the relatively more significant luminal amantadine efflux in the proximal tubules. Ranitidine did not enhance amantadine accumulation but produced inhibition at high concentrations. In proximal and distal tubule preparations, ranitidine (10 mM) increased Km from 86 +/- 7 to 121 +/- 8 and 95 +/- 5 to 160 +/- 10 microM, respectively (P less than .05), whereas Vmax was not changed (8.9 +/- 0.7 to 7.9 +/- 0.8 and 4.3 +/- 0.1 to 3.8 +/- 0.2 nmol/mg/min, respectively).