R B White1, H Heyn, J C Stevens. 1. Department of Drug Metabolism and Pharmacokinetics, Rhone-Poulenc Rorer Research and Development, Collegeville, Pennsylvania 19426-0107, USA.
Abstract
PURPOSE: RPR 102341 is structurally similar to the fluoroquinolone class of antibiotics. Because some fluoroquinolones have been shown to inhibit theophylline metabolism, concomitant administration may increase plasma levels of theophylline resulting in serious adverse effects. The purpose of this study was to determine if RPR 102341 affects theophylline metabolism in vitro and, thus, predict whether a clinically significant drug interaction is likely to occur. In addition, the effect of RPR 102341 on phenacetin O-deethylase activity was determined to address the enzymatic basis of a potential drug interaction. METHODS: The in vitro theophylline metabolism assay was conducted according to a modification of a published procedure. The phenacetin O-deethylase assay was conducted according to a modification of a published procedure. RESULTS: The rate of conversion of theophylline to 3-methylxanthine in human liver microsomes in the presence of 100 microM and 500 microM RPR 102341 was 93.6 and 106 percent of the control reactions, respectively. The formation of 1-methylxanthine was 97.6 and 100 percent of the control, and 1.3-dimethyluric acid formation was 88.9 and 95.2 percent of control at 100 microM and 500 microM RPR 102341, respectively. In agreement, RPR 102341 caused no inhibition of human liver CYP1A2-catalyzed phenacetin O-deethylase activity. Finally, no inhibition was observed when RPR 102341 was incubated with human liver microsomes and an NADPH regenerating system prior to the addition of theophylline. CONCLUSIONS: Based on these studies, RPR 102341 is not expected to cause significant drug interactions with theophylline.
PURPOSE: RPR 102341 is structurally similar to the fluoroquinolone class of antibiotics. Because some fluoroquinolones have been shown to inhibit theophylline metabolism, concomitant administration may increase plasma levels of theophylline resulting in serious adverse effects. The purpose of this study was to determine if RPR 102341 affects theophylline metabolism in vitro and, thus, predict whether a clinically significant drug interaction is likely to occur. In addition, the effect of RPR 102341 on phenacetin O-deethylase activity was determined to address the enzymatic basis of a potential drug interaction. METHODS: The in vitro theophylline metabolism assay was conducted according to a modification of a published procedure. The phenacetin O-deethylase assay was conducted according to a modification of a published procedure. RESULTS: The rate of conversion of theophylline to 3-methylxanthine in human liver microsomes in the presence of 100 microM and 500 microM RPR 102341 was 93.6 and 106 percent of the control reactions, respectively. The formation of 1-methylxanthine was 97.6 and 100 percent of the control, and 1.3-dimethyluric acid formation was 88.9 and 95.2 percent of control at 100 microM and 500 microM RPR 102341, respectively. In agreement, RPR 102341 caused no inhibition of human liver CYP1A2-catalyzed phenacetin O-deethylase activity. Finally, no inhibition was observed when RPR 102341 was incubated with human liver microsomes and an NADPH regenerating system prior to the addition of theophylline. CONCLUSIONS: Based on these studies, RPR 102341 is not expected to cause significant drug interactions with theophylline.
Authors: R A Robson; J O Miners; A P Matthews; I Stupans; D Meller; M E McManus; D J Birkett Journal: Biochem Pharmacol Date: 1988-05-01 Impact factor: 5.858
Authors: U Fuhr; G Strobl; F Manaut; E M Anders; F Sörgel; E Lopez-de-Brinas; D T Chu; A G Pernet; G Mahr; F Sanz Journal: Mol Pharmacol Date: 1993-02 Impact factor: 4.436