PHARMACOKINETICS, BIOAVAILABILITY, METABOLISM, TISSUE DISTRIBUTION AND URINARY-EXCRETION OF GAMMA-L-GLUTAMYL-L-DOPA IN THE RAT

Abstract— γ‐L‐Glutamyl‐L‐dopa (gludopa) is believed to be a dopamine prodrug specific for the kidney. Its pharmacokinetics have been studied in the rat given 50 mg kg−1 intravenously (i.v.) and 60 mg kg−1 intraperitoneally (i.p.). By the i.v. route, elimination followed apparent first order kinetics and was biphasic with a t 1/2α of 7 min and terminal half‐life of 67 min. After i.p. administration absorption was rapid (t 1/2ab 6 min), elimination was monophasic with a terminal half‐life almost identical following i.v. dosing (65 min), and bioavailability was 40%. In tissues (liver and kidney) gludopa was biotransformed to four intact catecholic products (L‐dopa, dopamine, DOPAC and γ‐L‐glutamyl‐dopamine) which appeared quickly (peaks at 15 min) and which were almost completely cleared by 4 h. Dopamine was the major kidney metabolite accounting for 69% of total catechol content with an AUC 31 times greater than in liver where it accounted for only 34% of total catechols. In rat urine eight major metabolites (5.7% of the dose) and at least 12 minor metabolites were detected of all of which 85% was dopamine. A higher percentage of the dose was excreted as intact catechols in man (15.7%) but fewer metabolites were detected (L‐dopa, dopamine, DOPAC). It is confirmed that gludopa is kidney specific in rat but that the pharmacological effects of dopamine are likely to be short lived due to rapid clearance. Gludopa appears to be less dopamine specific in man. 1990 Royal Pharmaceutical Society of Great Britain