Comparative renal excretion of VX-702, a novel p38 MAPK inhibitor, and methotrexate in the perfused rat kidney model.
BACKGROUND
VX-702 is a novel p38 mitogen-activated protein kinase inhibitor being developed to treat rheumatoid arthritis.


OBJECTIVE
To characterize the renal excretion profile of VX-702 using the isolated perfused rat kidney (IPRK) model.


METHODS
Studies were performed to assess the dose linearity of VX-702 excretion and to evaluate the effect of inhibitors of organic anion (probenecid) and organic cation (cimetidine) transport systems on VX-702 disposition. VX-702 excretion was studied over a range of doses targeting concentrations between 100 and 600 ng/mL. VX-702 (600 ng/mL) was also co-perfused with probenecid (1 mM) and cimetidine (2 mM). The results were compared to parallel experiments performed with methotrexate (MTX).


RESULTS
VX-702 excretion was linear over the range of doses studied, and clearance data were consistent with net reabsorption by the kidney. Transport inhibition studies indicate that VX-702 is not a substrate for renal organic anion and organic cation transport systems. MTX (500 ng/mL) also displayed net reabsorption in the IPRK, but secretory transport was inhibited upon co-administration with probenecid. This finding is consistent with previous IPRK studies that demonstrated inhibitory effects of NSAIDS on MTX excretion.


CONCLUSIONS
Overall, this study suggests that a renal drug-drug interaction between VX-702 and MTX would be unlikely if these medications were co-administered.
Tamhane
Mitalee
M
Division of Pharmaceutical Sciences, Long Island University, Brooklyn, NY 11201, USA.
Chakilam
Ananthsrinivas R
AR
Jayaraj
Andrew
A
Thakkar
Vineet
V
Taft
David R
DR
D000465:Algorithms; D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism*; D002927:Cimetidine / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007155:Immunologic Factors / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000502:physiology; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009994:Osmolar Concentration; D010477:Perfusion; D010671:Phenylurea Compounds / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014462:Ultrafiltration; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D010671:Phenylurea Compounds; C517771:VX 702; D002927:Cimetidine; D048051:p38 Mitogen-Activated Protein Kinases; D011339:Probenecid; D008727:Methotrexate