EFFECT OF NORFLOXACIN ON THEOPHYLLINE DISPOSITION - A COMPARISON WITHOTHER FLUOROQUINOLONES

The effects of norfloxacin (NOR), at steady-state plasma concentration s of 0-32 mg . l(-1), on the plasma clearance of a 6 . mg kg-l iv bolu s dose of theophylline (THEO) in the male Sprague-Dawley rat have been studied. The effects were characterised by a Ki value (Ki = 12 mu M), which was comparable with Ki values obtained previously under identic al conditions for ciprofloxacin, but higher than that obtained for eno xacin. The distributional characteristics, volume of distribution and liver to plasma concentration ratio, were very similar for the three c ompounds. The only marked pharmacokinetic differences were in hepatic clearance, where there was a rank order NOR > ciprofloxacin > enoxacin , a reverse of the order in the reduction of THEO clearance seen in cl inical studies. The advantages of using the steady-state experimental design described here are that equivalent concentrations are utilised to compare related drugs and differences in pharmacokinetics are accou nted for, to allow a direct comparison of potency. This information, t ogether with additional pharmacokinetic considerations, suggests that the different effects on THEO clearance seen in the clinic for NOR, ci profloxacin and enoxacin are not solely due to differences in inhibito ry potency, but also involve differences in hepatic clearance and henc e systemic availability of the fluoroquinolones.