EFFECT OF MORICIZINE ON THE PHARMACOKINETICS OF SINGLE-DOSE THEOPHYLLINE IN HEALTHY-SUBJECTS

We studied the effect of multiple oral doses of moricizine on the phar macokinetics of theophylline in healthy male subjects. Twelve subjects initially received two single oral doses of theophylline, one in the form of immediate-release Aminophyllin on day 1 and the other in the f orm of controlled-release Theo-Dur on day 3. Multiple oral doses of mo ricizine (Ethmozine, 250 mg every 8 h) began on day 5 and continued fo r 18 days. While receiving moricizine, the subjects were again given t he two formulations of theophylline in the same order on days 19 and 2 1. Theophylline pharmacokinetic profiles were obtained over 36 h after all theophylline administrations. Multiple-dose moricizine administra tion significantly decreased (p < 0.0005) theophylline area under the curve by 32 and 36% after Aminophyllin and Theo-Dur, respectively. The ophylline t1/2 was also significantly decreased (p < 0.02) by concomit ant moricizine dosing. Moricizine had no apparent effect on theophylli ne absorption after Aminophyllin, based on the lack of changes in the maximum plasma concentration (C(max)) and the time to reach C(max); ho wever, moricizine administration did decrease (p < 0.0005) the C(max) of theophylline after Theo-Dur. We conclude that these pharmacokinetic changes are most likely due to enzyme induction mediated by moricizin e. Consequently, concomitant use of moricizine and theophylline may ne cessitate the administration of more frequent and higher doses of theo phylline.