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

γ-L-glutamyl-L-DOPA (gludopa) is a dopamine prodrug that is relatively specific for the kidney. Because dopamine is phosphaturic, the present study compared the phosphaturic effects of the infusion of equimolar doses of gludopa (n = 8), L-DOPA (n = 8), and γ-L-glutamyl-L-tyrosine (glutyrosine, n = 6). Glutyrosine was used as a control to evaluate the effect of the glutamyl portion of gludopa on phosphate excretion. Sprague-Dawley rats (350 to 400 g) were anesthetized with 5-sec-butyl-ethyl-2-thyobarbituric acid (Inactin; 100 mg/kg, IP) and underwent thyroparathyroidectomy. Clearances were taken during the infusion of normal saline vehicle, followed by the infusion of gludopa, L-DOPA, or glutyrosine, all infused at the rate of 10 nmol/kg bolus and 0.8 nmol/kg/min (IV). To determine the contribution of glutamyl derivative to phosphate excretion, gludopa or L-DOPA was infused in the presence of SCH23390, a DA-1 receptor antagonist. Gludopa infusion significantly increased dopamine excretion (from 1.9 ± 0.2 ng/min to 17.0 ± 3.9 ng/min, Δ15.0 ± 3.9 ng/min, P < .008) and fractional excretion of phosphate (from 2.6% ± 0.6% to 34.8% ± 1.8%, Δ32.0% ± 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, Δ8.3 ± 1.5 ng/min, P < .001) and fractional excretion of phosphate (from 1.7% ± 0.6% to 8.2% ± 2.0%, Δ6.4% ± 1.5%, P < .004). Glutyrosine infusion significantly increased fractional excretion of phosphate (from 2.8% ± 0.8% to 17.5% ± 5.2%, Δ14.6% ± 4.8%, P < .03) without changing dopamine excretion (Δ0.5 ± 0.2 ng/min). Infusion of gludopa in the presence of SCH23390 increased fractional excretion of phosphate (from 5.7% ± 2.5% to 12.6% ± 3.5%, Δ6.8% ± 2.3%, n = 6, P < .03), whereas SCH23390 completely blocked the phosphaturic effect of L-DOPA. We conclude that γ-L-glutamyl-L-DOPA is more phosphaturic than L-DOPA in the rat because of the combined effects of dopamine and the glutamyl moiety.