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Indometacin farnesil (Indo-F) is a prodrug of indomethacin designed to reduce the occurrence of side-effects by esterification of the carboxyl group on indomethacin with farnesol. We have examined the pharmacological kinetics and action of Indo-F in peripheral blood mononuclear cells (PBMNC) and polymorphonuclear leukocytes (PBPNL) from patients with rheumatoid arthritis (RA). PBMNC and PBPNL were obtained from 31 RA patients. Indo-F was incubated with PBMNC or PBPNL in the presence or absence of granulocyte-macrophage colony stimulating factor (GM-CSF) (100 pg/ml) for 3 approximately 7 days, after which the concentrations of Indo-F and indomethacin in the culture supernatants or in the cytoplasm extracts were measured with HPLC. The levels of Indo-F in the culture supernatants were significantly decreased in the presence of PBMNC or PBPNL from either normal individuals or RA patients. Indo-F was found to be taken up by PBMNC as well as by PBPNL from RA patients. Conversion of Indo-F into indomethacin was significantly enhanced by GMCSF in the presence of PBMNC, but not PBPNL. The results indicate that Indo-F is taken up by peripheral blood leukocytes from RA patients. Moreover, the data suggest that monocyte-lineage cells might play an important role in the conversion of Indo-F into indomethacin since GM-CSF markedly facilitated the conversion in the presence of PBMNC, but not PBPNL.

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Interaction of indometacin farnesil, a new nonsteroidal antiinflammatory drug with peripheral blood mononuclear cells from patients with rheumatoid arthritis.