PMID- 15801548
OWN - NLM
STAT- MEDLINE
DCOM- 20050719
LR  - 20190911
IS  - 0049-8254 (Print)
IS  - 0049-8254 (Linking)
VI  - 34
IP  - 11-12
DP  - 2004 Nov-Dec
TI  - Renal elimination of a novel and potent alphavbeta3 integrin antagonist in 
      animals.
PG  - 1059-74
AB  - 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.
FAU - Prueksaritanont, T
AU  - Prueksaritanont T
AD  - Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, 
      USA. thomayant_prueksaritanont@merck.com
FAU - Hochman, J H
AU  - Hochman JH
FAU - Meng, Y
AU  - Meng Y
FAU - Pudvah, N T
AU  - Pudvah NT
FAU - Barrish, A
AU  - Barrish A
FAU - Ma, B
AU  - Ma B
FAU - Yamazaki, M
AU  - Yamazaki M
FAU - Fernandez-Metzler, C
AU  - Fernandez-Metzler C
FAU - Lin, J H
AU  - Lin JH
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - England
TA  - Xenobiotica
JT  - Xenobiotica; the fate of foreign compounds in biological systems
JID - 1306665
RN  - 0 
      (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)
RN  - 0 (Imidazoles)
RN  - 0 (Integrin alphaVbeta3)
RN  - 0 (Naphthyridines)
SB  - IM
MH  - Animals
MH  - Female
MH  - Imidazoles/*pharmacokinetics
MH  - Integrin alphaVbeta3/*antagonists & inhibitors
MH  - Kidney/*metabolism
MH  - Macaca mulatta
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Naphthyridines/*pharmacokinetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Species Specificity
EDAT- 2005/04/02 09:00
MHDA- 2005/07/20 09:00
CRDT- 2005/04/02 09:00
PHST- 2005/04/02 09:00 [pubmed]
PHST- 2005/07/20 09:00 [medline]
PHST- 2005/04/02 09:00 [entrez]
AID - 10.1080/00498250400015277 [doi]
PST - ppublish
SO  - Xenobiotica. 2004 Nov-Dec;34(11-12):1059-74. doi: 10.1080/00498250400015277.