Renal selective N-acetyl-L-gamma-glutamyl prodrugs: studies on the selectivity of some model prodrugs.
1. In this study, a number of structurally different N-acetyl-L-gamma-glutamyl prodrugs were investigated with respect to selective uptake by the kidney in male Wistar rats. 2. All prodrugs were tested in vitro in rat kidney slices and kidney homogenate to study their uptake and conversion. It was found that the prodrugs of para-nitroaniline (agPNA), aminophenyl acetic acid (agAFA), sulphamethoxazole (agSM), sulphadimethoxine (agSDM), propranolol (agPP) and metoprolol (agMP) were accumulated by a probenecid-sensitive carrier. The prodrug of 4'-aminoantipyrine (agAAP) was not accumulated by a probenecid- or buthionine sulphoximine-sensitive carrier. Unlike all other prodrugs, agAAP and agMP were not, or only a very limited extent converted to the parent compound in vitro. 3. agPNA, agAFA and agPP were also investigated in vivo. The tissue distribution of the prodrugs and the parent drugs was established, as was their urinary excretion and pharmacokinetic behaviour. agPNA and agAFA showed selective uptake by the kidney, in contrast to agPP which accumulated in the liver. The distribution of the parent compounds following prodrug administration was as follows: agPNA was found in kidney and plasma: agAFA in kidney only; agPP in liver only. 4. The factors which determine the selectivity of N-acetyl-L-gamma-glutamyl prodrugs are discussed. The main factors are: the transport into the kidney, the conversion rate, the residence time of the prodrug in the kidney and the presence or absence of competition for uptake and conversation by other tissues, e.g. the liver. It is concluded that this prodrug approach offers the possibility of delivering drugs selectively to the kidney, but also that it is not universally applicable.
Drieman
J C
JC
Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
Thijssen
H H
HH
Struyker-Boudier
H A
HA
D000675:Ampyrone / Q000493:pharmacokinetics / Q000652:urine; D000814:Aniline Compounds / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D010648:Phenylacetates / Q000493:pharmacokinetics* / Q000652:urine; D011355:Prodrugs / Q000493:pharmacokinetics*; D011433:Propranolol / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D013412:Sulfadimethoxine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D013420:Sulfamethoxazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D014018:Tissue Distribution
D000814:Aniline Compounds; D010648:Phenylacetates; D011355:Prodrugs; D000675:Ampyrone; C019498:4-nitroaniline; D013412:Sulfadimethoxine; D011433:Propranolol; D008790:Metoprolol; D013420:Sulfamethoxazole