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.
Raoul
Jennifer M
JM
Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Peterson
Marc R
MR
Peterson
Theresa C
TC
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010431:Pentoxifylline / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013997:Time Factors
D000890:Anti-Infective Agents; D010726:Phosphodiesterase Inhibitors; D002939:Ciprofloxacin; D010431:Pentoxifylline