RT Journal Article
SR Electronic
T1 Effect of DQ-2556, a new cephalosporin, on organic ion transport in renal plasma membrane vesicles from the dog, rabbit and rat.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 436
OP 441
VO 255
IS 2
A1 P P Sokol
YR 1990
UL http://jpet.aspetjournals.org/content/255/2/436.abstract
AB The effect of the new cephalosporin antibiotic DQ-2556 [(6R, 7R)-7-[(Z)-2-(2-aminothiazol-4-yl-2-(methoxyimino)acetamido]-3-[4- (oxazol-5-yl)-1-pyridinio]methyl-8-oxo-5-thia-1-azabicyclo[4 .2.0]oct-2- ene--2-carboxylate] on the transport of organic cations (N1-[3H]methylnicotinamide, NMN and [3H]tetraethylammonium), organic anions ([3H]p-aminohippurate) and dipeptides ([14C]glycylsarcosine) was examined in brush border membrane vesicles (BBMV) and basolateral membrane vesicles from the dog, rabbit and rat. In BBMV, DQ-2556 was more effective in cis-inhibiting the uptake of NMN in the rat than in the dog. No effect was seen in the rabbit. DQ-2556 had no effect on brush border transport systems for organic anions or dipeptides and basolateral transport systems for organic cations or anions in dogs, rabbits and rats. In contrast, cephaloridine, a nephrotoxic cephalosporin, inhibited NMN and p-aminohippurate uptake in dog BBMV and basolateral membrane vesicles, respectively. Cephaloridine had no effect on the other organic ion transport systems in the species being tested. A dose-response curve was constructed for DQ-2556 inhibition of NMN transport in rat BBMV. An IC50 value of 2.5 mM was obtained. In counterflow studies DQ-2556 did not demonstrate trans- stimulation of tetraethylammonium uptake. Kinetic studies revealed that DQ-2556 increased the Km value of NMN from 130 to 190 microM, while having no effect on the Vmax value (1.72 nmol/min x mg of protein vs. 1.75 nmol/min x mg of protein in the presence of DQ-2556). These data are most consistent with DQ-2556 being a low affinity competitive inhibitor of NMN transport in rat BBMV.