Renal elimination of a novel and potent alphavbeta3 integrin antagonist in animals.
Compound A (3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]napthyridin-2-yl)propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid), a hydrophilic zwitter-ion, is a potent and selective alphavbeta3 integrin antagonist currently under clinical development for the treatment of osteoporosis. The mechanism of renal excretion of compound A was investigated using a combination of in vivo and in vitro approaches. In rats, renal excretion of compound A involved tubular secretion; ratios between renal clearance, corrected for unbound fraction in plasma (CLr,u) and glomerular filtration rate (GFR) were greater than unity (2-5). The tubular secretion of compound A was saturable at high plasma levels (> 26 microM), and was inhibited significantly, although modestly (about twofold) by relatively high plasma concentrations of the organic anion PAH (160 microM) and the cation cimetidine (about 400 microM), but not by the P-gp inhibitor quinidine (about 50 microM). However, compound A (about 100 microM) had a minimal effect on CLr/GFRs for cimetidine and PAH. In rhesus monkeys, renal elimination of compound A also involved tubular secretion, with a CLr,u/GFR ratio of about 30. The renal secretion of compound A was not affected by either cimetidine (about 120 microM) or PAH (about 80 microM). Similarly, compound A (about 40 microM) had a minimal effect on the renal tubular secretion of both cimetidine and PAH. At the doses studied, neither rat nor monkey plasma protein binding of compound A, cimetidine or PAH was affected in the presence of each other. In vitro transport studies showed that compound A was not a substrate for P-gp in the Caco-2, human MDR1 and mouse mdr1a transfected LLC-PK1 cell lines. In an uptake study using rOAT1 and rOAT3 transfected HEK cell lines, compound A was shown to be a substrate for rat OAT3 (Km= 15 microM), but not rat OAT1. The results suggest that the tubular secretion of compound A is not mediated by P-gp, but rather is mediated, at least in part, via the organic anion transporter OAT3, the renal transporter shown to be capable of transporting both the organic anion PAH and the organic cation cimetidine. Although there is a possibility for pharmacokinetic interactions between compound A and substrates or inhibitors of OAT3, at the renal excretion level, the magnitude of interaction would likely be modest in humans at clinically relevant doses.
Prueksaritanont
T
T
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA. thomayant_prueksaritanont@merck.com
Hochman
J H
JH
Meng
Y
Y
Pudvah
N T
NT
Barrish
A
A
Ma
B
B
Yamazaki
M
M
Fernandez-Metzler
C
C
Lin
J H
JH
D000818:Animals; D005260:Female; D007093:Imidazoles / Q000493:pharmacokinetics*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D009287:Naphthyridines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
C502128:3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-(1,8)napthyridin-2-yl)propyl)imidazolidin-1-yl)-3(S)-(6-methoxypyridin-3-yl)propionic acid; D007093:Imidazoles; D039302:Integrin alphaVbeta3; D009287:Naphthyridines