Renal clearance of substituted hippurates in the dog. II. 4-Amino-, hydroxy- and methoxy-substituted benzoylglycines.
Plasma kinetics and renal excretion of 4-aminobenzoylglycine (p-aminohippurate), hydroxy- and methoxy-substituted benzoylglycines were studied in three Beagle dogs after rapid i.v. administration of about 1 g. Plasma protein binding of 4-amino-, 3-hydroxy- and 4-hydroxybenzoylglycine was low (less than 15%) and practically constant over a range of 5 to 450 micrograms/ml, whereas the 2-hydroxy analog showed concentration-dependent protein binding (40-80%). The excretory patterns of the 4-amino, 3- and 4-hydroxy analogs were essentially the same; rapid elimination from plasma into urine (greater than 80% of the dose), mainly by very efficient supply-limited tubular secretion. Conversely, the excretion of 2-hydroxybenzoylglycine was characterized by a lower plasma clearance and total renal excretion (64% of the dose), and a limited capacity of the tubular secretory system. The methoxybenzoylglycines showed nonlinear plasma protein binding varying between 10 and 70%, rapid clearance from plasma, largely by renal excretion (72-84% of the administered dose). Tubular secretion of 2- and 3-methoxybenzoylglycine was saturated, whereas complete saturation was not achieved for the 4-methoxy isomer. The kinetic parameters of tubular secretion were estimated with a physiologically based kidney model: 2-hydroxy, tubular transport maximum (TM) = 4.4 +/- 0.9 mg/min, Michael-Menten constant of the tubular secretion mechanism (KT) = 23 +/- 8 micrograms/ml; 2-methoxy-TM = 11.7 +/- 4.9 mg/min, KT = 42 +/- 9 micrograms/ml; 3-methoxy-TM = 8.8 +/- 1.0 mg/mn, KT = 27 +/- 20 micrograms/ml. Inasmuch as secretion of the other compounds was not saturated, only the intrinsic secretion clearance (CLint) = TM/KT could be estimated; 4-amino-CLint = 145 +/- 50 ml/min, 3-hydroxy-CLint = 194 +/- 21 ml/min, 4-hydroxy-CLint = 153 +/- 23 ml/min and 4-methoxy-CLint = 201 +/- 47 ml/min. The 4-methoxy isomer was metabolized to some extent by deconjugation of the glycine moiety and the resulting benzoate was found in plasma but not in urine.(ABSTRACT TRUNCATED AT 250 WORDS)
Russel
F G
FG
Department of Pharmacology, University of Nijmegen, The Netherlands.
Wouterse
A C
AC
van Ginneken
C A
CA
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D005998:Glycine / Q000378:metabolism; D006626:Hippurates / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D013329:Structure-Activity Relationship
D001798:Blood Proteins; D006626:Hippurates; D005998:Glycine