Renal selective N-acetyl-L-gamma-glutamyl prodrugs. III. N-acetyl-L-gamma-glutamyl-4'-aminowarfarin is not targeted to the kidney but is selectively excreted into the bile.
The pharmacokinetics of N-acetyl-L-gamma-glutamyl-4'-aminowarfarin (AGAW) was studied in the rat. The aim of this prodrug was to cause a renal-specific inhibition of the vitamin K cycle as a result of renal-specific release of the active drug 4'-aminowarfarin (AW). In vitro, it was found that kidney and liver homogenates and cytosol were able to convert the prodrug. In vivo, plasma concentrations of AW rose only slowly after a dose of 10 mg/kg AGAW i.v. to give a maximum concentration of about 3 micrograms AW/ml at t = 14 to 24 h. The tissue distribution of AGAW and AW was measured after 10 mg/kg AGAW i.v. It was found that AGAW did not accumulate in the kidney (9.7 micrograms/g in the kidney; 83 micrograms/ml in plasma at t = 60 min). AW concentrations were very low (0.1 microgram/ml or mg at t = 60 min). These results suggest that AGAW is not transported via a carrier into the kidney. The uptake of AGAW in vitro by rat kidney slices was investigated. It was found that AGAW did not accumulate in the slices. Neither did AGAW influence the accumulation of N-acetyl-gamma-glutamyl sulfamethoxazole in kidney slices. A second explanation for the lack of selectivity of AGAW in vivo could be its high (approximately 90%) plasma protein binding. Instead of being targeted to the kidney, however, AGAW was found to be excreted via a carrier-mediated mechanism into the bile: 50% of the dose was recovered unchanged in the bile within 3 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
J C
JC
Drieman
H H
HH
Thijssen
D000818:Animals; D001646:Bile / Q000378:metabolism*; D019328:Buthionine Sulfoximine; D007208:Indocyanine Green / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009928:Organ Specificity; D011339:Probenecid / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014812:Vitamin K / Q000378:metabolism; D014859:Warfarin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
D011355:Prodrugs; D014812:Vitamin K; C071743:N-acetyl-gamma-glutamyl-4'-aminowarfarin; D008717:Methionine Sulfoximine; C038441:3-(1-(4-aminophenyl)-3-oxobutyl)-4-hydroxy-2H-1-benzopyran-2-one; D019328:Buthionine Sulfoximine; D014859:Warfarin; D007208:Indocyanine Green; D011339:Probenecid