Renal selective N-acetyl-gamma-glutamyl prodrugs. II. Carrier-mediated transport and intracellular conversion as determinants in the renal selectivity of N-acetyl-gamma-glutamyl sulfamethoxazole.
The mechanism of activation of the prodrug N-acetyl-L-gamma-glutamyl sulfamethoxazole (AGSM) and of gamma-glutamyl sulfamethoxazole (GSM) as a model for the mechanism of the renal selectivity of N-acetyl-gamma-glutamyl prodrugs was investigated. The hypothesis was tested that this selectivity is due largely to a carrier-mediated transport followed by an intracellular conversion of the prodrug to the active drug, in contrast to another mechanism. The transport of AGSM and GSM was studied with the use of kidney slices. AGSM accumulated in the slices. At 75 microM substrate concentration, the slice to medium ratio was 2.5 +/- 0.2. This accumulation was inhibited by the anion transport inhibitor probenecid (82% inhibition at 1.0 mM) and by the gamma-glutamyl transport inhibitor buthionine sulfoximine (60% at 1.0 mM). Acivicin, L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid did not inhibit AGSM accumulation at 0.1 mM, a concentration sufficient to inhibit the enzyme gamma-glutamyl transpeptidase; at 1.0 mM, however, AGSM accumulation was inhibited by 44%. These results suggest that the accumulation of AGSM is caused by an active transport process. GSM did not accumulate in the slices, but was completely converted to sulfamethoxazole (SM) after a 90-min incubation. Accumulation of AGSM was also seen in vivo: at 20 min after AGSM administration (10 mg.kg-1) the plasma, kidney and liver concentrations were 73 +/- 6, 110 +/- 7 and 37 +/- 5 micrograms.g-1, respectively. This accumulation could be inhibited by buthionine sulfoximine but not by acivicin.(ABSTRACT TRUNCATED AT 250 WORDS)
Drieman
J C
JC
Department of Pharmacology, University of Limburg, Masstricht, The Netherlands.
Thijssen
H H
HH
Struyker-Boudier
H A
HA
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D019328:Buthionine Sulfoximine; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006207:Half-Life; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000187:drug effects; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology
D000963:Antimetabolites; D007555:Isoxazoles; D011355:Prodrugs; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C063527:gamma-glutamylsulfamethoxazole; C063526:N-acetyl-glutamylsulfamethoxazole; D005723:gamma-Glutamyltransferase; D013420:Sulfamethoxazole; C006303:acivicin