The pharmacokinetics of γ‐glutamyl‐l‐dopa in normal and anephric rats and rats with glycerol‐induced acute renal failure

Abstract

AB9 2ZD and tDepartment of Clinical Pharmacology, The Royal Infirmary, Edinburgh EH3 9YW1 The pharmacokinetics of y-glutamyl-L-dopa (gludopa) and its metabolite, L-dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg-1, 5 mg kg-1 and 7.5 mg kg-'. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol-induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg 1.2 Gludopa was extensively metabolised to L-dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 + 9.6 ml min -1 kg1 and elimination rate constant of 2.99 + 0.27h1. The mean residence time and half-life were 20.9 + 1.4 and 14.4 + 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 + 0.181 kg -. 3 No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite L-dopa. 4 In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite L-dopa, respectively. 5 These results confirm that gludopa is an efficient pro-drug for L-dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.

Regional haemodynamic effects of dopamine and its prodrugs l‐dopa and gludopa in the rat and in the glycerol‐treated rat as a model for acute renal failure

“…This metabolism occurs predominantly in the kidney (Barthelmebs et al, 1990;Boateng et al, 1990;Cummings et al, 1990). The effects of gludopa on the kidney have been described by several investigators in normal rats (Wilk et al, 1978;, rats with decreased renal function (Casson et al, 1982;1983;Boateng et al, 1990;Barthelmebs et al, 1991), rabbit (Wang, Z.-Q. et al, 1992) and man (Jeffrey et al, 1988a;Casagrande et al, 1989;MacDonald et al, 1989).…”

“…Pharmacokinetic studies with gludopa in the rat support our pharmacodynamic findings. After a bolus injection of gludopa, considerable amounts of L-dopa and dopamine were found in plasma (Boateng et al, 1990;Cummings et al, 1990). Due to the short halflife time of dopamine, it is difficult to estimate the amount of dopamine that is available systemically in vivo.…”

“…It is converted by y-glutamyl transpeptidase to L-dopa and subsequently by aromatic aminoacid decarboxylase to dopamine. This metabolism occurs predominantly in the kidney (Barthelmebs et al, 1990;Boateng et al, 1990;Cummings et al, 1990). The effects of gludopa on the kidney have been described by several investigators in normal rats (Wilk et al, 1978;, rats with decreased renal function (Casson et al, 1982;1983;Boateng et al, 1990;Barthelmebs et al, 1991), rabbit (Wang, Z.-Q.…”

“…The dose of gludopa was not adjusted to the decreased kidney function, since the pharmacokinetics of gludopa are not changed in rats with glycerol-induced ARF (Boateng et al, 1990). The renal effects of gludopa in glycerol-induced ARF in rats are different from those in normal rats.…”

The renal handling of dopamine originating from l‐DOPA and γ‐glutamyl‐l‐DOPA

“…Neither dopamine nor its precursor L-DOPA appear; however, particularly suitable for the correction of the hypothetical deficit of renal dopaminergic mechanisms in hypertension, mainly because of their extrarenal actions (Lee, 1988). T-Glutamyl-L-DOPA (GluDOPA), on the other hand, is a synthetic dipeptide which also gives origin to dopamine (Wilk et al, 1978;Worth et al, 1985;Boateng et al, 1990;Soares-da-Silva et al, 1992b). GluDOPA itself is devoid of pharmacological actions but it is converted, preferentially in the kidney, to L-DOPA and subsequently to dopamine by thb sequential actions of the brush border enzyme y-glutamyl transpeptidase (y-GT) and the intracellular AAAD (Lee, 1988).…”