A novel drug interaction between the quinolone antibiotic ciprofloxacin and a chiral metabolite of pentoxifylline

Pentoxifylline (PTX), a methylxanthine derivative, is metabolized to seven compounds in vivo, with metabolites 1 and 5 possessing biologic activity. Metabolite-1 is a chiral molecule and its S-enantiomer is selectively formed during PTX metabolism in vivo. We have developed a reproducible method of synthesizing a racemic mixture of the chiral metabolite-1 (M-1) of PTX. In this study, we examined the kinetics of racemic M-1 in mice compared to PTX. An interaction between PTX and the quinolone antibiotic ciprofloxacin has been demonstrated. A goal of this study was to determine if a similar interaction occurs between ciprofloxacin and M-1 in vivo. M-1 and PTX had similar absorption and elimination rates. M-1 was rapidly converted to PTX, while very little PTX was converted to M-1 in vivo. The peak concentration of biologically active drug (PTX + M-1) was 36% higher when M-1 was administered compared to PTX. Combination of ciprofloxacin and PTX significantly increased serum concentrations of both PTX and M-1 (2-fold) compared to controls. The combination of M-1 and ciprofloxacin significantly increased serum concentration of M-1 (3-fold) and PTX (2-fold). The ciprofloxacin/M-1 combination produced a significantly higher sera concentration of bioactive drug compared to all other groups suggesting that this combination may enhance the anti-fibrogenic effect.