Effect of gamma-L-glutamyl-L-DOPA on phosphate excretion

gamma-L-glutamyl-L-DOPA (gludopa) is a dopamine prodrug that is relatively specific for the kidney. Because dopamine is phosphaturic, the present stud y compared the phosphaturic effects of the infusion of equimolar doses of g ludopa (n = 8), I-DOPA (n = 8), and gamma-L-glutamyl-L-tyrosine (glutyrosin e, n = 6). Glutyrosine was used as a control to evaluate the effect of the glutamyl portion of gludopa on phosphate excretion. Sprague-Dawley rats (35 0 to 400 g) were anesthetized with 5-sec-butylethyl-2-thyobarbituric acid ( Inactin; 100 mg/kg, lp) and underwent thyroparathyroidectomy. Clearances we re taken during the Infusion of normal saline vehicle, followed by the infu sion of gludopa, L-DOPA, or glutyrosine, all Infused at the rate of 10 nmol /kg bolus and 0.8 nmol/kg/min (rv). To determine the contribution of glutam yl derivative to phosphate excretion, gludopa or L-DOPA was infused in the presence of SCH23390, a DA-1 receptor antagonist. Gludopa infusion signific antly increased dopamine excretion (from 1.9 +/- 0.2 ng/min to 17.0 +/- 3.9 ng/min, Delta 15.0 +/- 3.9 ng/min, P < .008) and fractional excretion of p hosphate (from 2.6% +/- 0.6% to 34.8% +/- 1.8%, Delta 32.0% +/- 1.6%, P < . 001). L-DOPA infusion significantly increased dopamine excretion (from 1.4 +/- 0.4 ng/min to 9.7 +/- 1.6 ng/min, Delta 8.3 +/- 1.5 ng/min, P < .001) a nd fractional excretion of phosphate (from 1.7% +/- 0.6% to 8.2% +/- 2.0%, Delta 6.4% +/- 1.5%, P < .004). Glutyrosine infusion significantly increase d fractional excretion of phosphate (from 2.8% +/- 0.8% to 17.5% +/- 5.2%, Delta 14.6% +/- 4.8%, P < .03) without changing dopamine excretion (Delta 0 .5 +/- 0.2 ng/min). Infusion of gludopa in the presence of SCH23390 increas ed fractional excretion of phosphate (from 5.7% +/- 2.5% to 12.6% +/- 3.5%, Delta 6.8% +/- 2.3%, n = 6, P < .03), whereas SCH23390 completely blocked the phosphaturic effect of L-DOPA. We conclude that gamma-L-glutamyl-L-DOPA is more phosphaturic than L-DOPA in the rat because of the combined effect s of dopamine and the glutamyl moiety.