Disposition of the bromosulfophthalein-glutathione conjugate in the isolated perfused rat kidney.
Renal elimination of the bromosulfophthalein-glutathione conjugate (BSP-GSH) after its i.v. administration in the rat in vivo is negligible. In our study we wanted to establish whether the high albumin-binding of BSP-GSH constitutes the major restrictive factor toward the urinary excretion of the compound. The renal disposition of BSP-GSH was studied in the isolated rat kidney during perfusions with or without albumin in the perfusate. The urinary clearance of BSP-GSH in the absence of albumin was very low (< 60 microliters/min) as compared to the inulin clearance (approximately 300 microliters/min). This indicates that albumin-binding is not the major reason for the low urinary clearance of BSP-GSH. Addition of albumin to the perfusate further decreased the urinary excretion by 60%. BSP-GSH is metabolized by the kidney into two major metabolites: the cysteinylglycine conjugate and the di-glutathione conjugate. Both metabolites appear in perfusate, which suggests that BSP-GSH undergoes tubular (re-)uptake. The di-glutathione conjugate is further metabolized to the di-cysteinylglycine conjugate. The di-glutathione conjugate and the di-cysteinylglycine conjugate are the major urinary components and the urinary elimination of BSP-GSH may depend on their formation. Inhibition of gamma-glutamyl transpeptidase activity with acivicin largely prevented the degradation to the cysteinylglycine and dicysteinylglycine conjugates of BSP. The total rate of urinary excretion, however, was only slightly lowered by acivicin. Apparently, cleavage of the gamma-glutamyl moiety is not relevant for the total urinary elimination of BSP-GSH.
Snel
C A
CA
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Moons
M M
MM
Russel
F G
FG
Mulder
G J
GJ
D000418:Albumins / Q000378:metabolism; D000818:Animals; D005978:Glutathione / Q000493:pharmacokinetics* / Q000652:urine; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism* / Q000502:physiology; D008297:Male; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013448:Sulfobromophthalein / Q000493:pharmacokinetics*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D000418:Albumins; D007555:Isoxazoles; D013448:Sulfobromophthalein; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin