Abstract

Plasma kinetics and renal excretion of benzoylglycine (hippurate) and methyl-substituted benzoylglycines were studied in three Beagle dogs, after rapid i.v. administration of about 1 g of glycine conjugate. Benzoylglycine and the 3- and 4-methyl analogs showed nonlinear plasma protein binding varying between 20 and 80% over a concentration range of 5 to 450 micrograms/ml. For 2-methylbenzoylglycine an extremely high protein binding, practically approaching 100%, was observed at low plasma levels (less than 50 micrograms/ml). All conjugates were cleared largely via the kidney (greater than 80% of the dose) and, except for the 2-methyl analog, eliminated rapidly from plasma. Plasma concentration and renal excretion rate data were analyzed simultaneously with a previously developed physiologically based kidney model. Tubular secretion appeared to be a function of the total drug concentration in renal plasma, except for 2-methylbenzoylglycine, presumably due to its tight protein binding. The average values of the parameters characterizing the tubular transport maximum (TM in milligrams per minute) and the apparent affinity for the secretory system (KT in micrograms per milliliter) were: benzoylglycine TM = 5.5 +/- 0.8, KT = 40 +/- 5; 3-methylbenzoylglycine TM = 7.1 +/- 3.3, KT = 49 +/- 1; 4-methylbenzoylglycine TM = 8.0 +/- 1.6, KT = 14 +/- 6. Secretion of 2-methylbenzoylglycine was not saturated. Accordingly, only the ratio TM/KT = 163 +/- 54 ml/min could be calculated. An interesting observation was the partial deconjugation of 4-methylbenzoylglycine to its corresponding benzoate.(ABSTRACT TRUNCATED AT 250 WORDS)