Tenidap and flurbiprofen enhance uptake of matrix metalloproteinase inhibitor 4-dedimethylaminotetracycline in inflamed joints of adjuvant arthritic rats.

Abstract

To identify a mechanism by which a matrix metalloproteinase (MMP) inhibitor might act synergistically with other agents to decrease MMP activity and thereby lessen the radiologic severity of adjuvant arthritis. Rats with adjuvant arthritis were treated with either flurbiprofen (FBP) or tenidap (TDP), along with 4-dedimethylaminotetracycline (CMT-1), a potent MMP inhibitor. Indices of inflammatory severity and of radiologic destruction were assessed and compared to serum and bone levels of the MMP inhibitor. Combination therapy with the MMP inhibitor plus either of the other drugs led to synergistic improvement in radiologic severity. For example, CMT-1 combined with TDP reduced radiologic severity 45% while decreasing collagenase and gelatinase activities by 61 and 72%, respectively, more than doubling bone CMT-1 levels (7.6 micrograms/g to 16.4 micrograms/g). FBP had similar effects. MMP inhibitors need access to the arthritic joint to interact with their target enzymes. Concomitant antiinflammatory therapy is required to assure drug entry into the inflamed tissues.