Comparative renal excretion of VX-702, a novel p38 MAPK inhibitor, and methotrexate in the perfused rat kidney model.

Abstract

CONTEXT:

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.

CONCLUSION:

Overall, this study suggests that a renal drug-drug interaction between VX-702 and MTX would be unlikely if these medications were co-administered.

• Authors: Mitalee Tamhane, Ananthsrinivas R Chakilam, Andrew Jayaraj, Vineet Thakkar, David R Taft
• Journal: Drug development and industrial pharmacy (Drug Dev Ind Pharm) Vol. 36 Issue 3 Pg. 315-22 (Mar 2010) ISSN: 1520-5762 [Electronic] England
• PMID: 20170280 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Enzyme Inhibitors
• Immunologic Factors
• Organic Anion Transporters
• Organic Cation Transport Proteins
• Phenylurea Compounds
• VX 702
• Cimetidine
• p38 Mitogen-Activated Protein Kinases
• Probenecid
• Methotrexate

Topics

• Algorithms
• Animals
• Antirheumatic Agents (metabolism)
• Cimetidine (pharmacology)
• Drug Interactions
• Enzyme Inhibitors (analysis, chemistry, metabolism)
• Glomerular Filtration Rate (drug effects)
• Immunologic Factors (metabolism)
• Kidney (drug effects, metabolism)
• Kinetics
• Male
• Methotrexate (analysis, chemistry, metabolism)
• Organic Anion Transporters (antagonists & inhibitors, physiology)
• Organic Cation Transport Proteins (antagonists & inhibitors, physiology)
• Osmolar Concentration
• Perfusion
• Phenylurea Compounds (analysis, chemistry, metabolism)
• Probenecid (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Ultrafiltration
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)