KW-4490

1. The pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor, were investigated in rats and monkeys. After oral administration, KW-4490 was rapidly absorbed, and then its plasma concentrations apparently declined with half-lives of approximately 5 h in rats and 3.5 h in cynomolgus monkeys; however, a number of secondary peaks were apparent in the profiles for both species. The plasma pharmacokinetics of KW-4490 were comparable between rats and monkeys. 2. After oral administration, KW-4490 was mainly eliminated by metabolism to acylglucuronides and renal excretion in the unchanged form. KW-4490 acylglucuronides were found in monkey but not rat urine. In rats, KW-4490 acylglucuronides were excreted only in bile. Although the pathway of excretion of acylglucuronides differed between rats and monkeys, cumulative excretion in the two animals was very similar, as expected from comparable hepatic clearance for glucuronidation in rat and monkey liver microsomes. 3. The glomerular filtration rate of unbound KW-4490 indicated that renal tubular secretion was significant in monkeys, whereas reabsorption was significant in rats. These species differences in urinary excretion of KW-4490 and its acylglucuronide metabolites are most likely due to substrate specificity of active transporters in rat and monkey kidney.

A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA). Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4) inhibitors in a new animal model for the evaluation of pannus formation and cytokine production in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA) were challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution in the back of the mice. Drugs were orally administered for 10 days. The granuloma formed around the filter was collected on day 11. It was chopped into pieces and cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type of cytokines produced in the granuloma was quite similar to those produced in pannus in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production of IL-1β, TNF-α, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors more strongly suppressed IL-12 production and the increase in myeloperoxidase activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-αand IL-12 production from thioglycolate-induced murine peritoneal macrophages and the proliferation of rat synovial fibroblasts. These results indicate this model makes it easy to evaluate the effect of drugs on various cytokine productions in a granuloma without any purification step and may be a relevant model for evaluating novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have therapeutic effects on pannus formation in RA by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.