Pharmacokinetics of theophylline and 3-methylxanthine in guinea pigs. II. Multiple dose administration

Following intravenous bolus injection of theophylline 2.37 . 10(-) mol kg-1 to guinea pigs (administered as aminophylline 52.0 mg kg-1), the elimination of the dose was more rapid in a group of 8 guinea pigs that had received theophylline 2.02 . 10(-4) mol kg-1 (aminophylline 44.3 mg kg-1 (aminophylline 44.3 mg kg-1) intraperitoneally twice daily for 12 days prior to the experiment than in a group of 10 non-pretreated guinea pigs of the same age. The difference was statistically significant in Student's t-test (P less than 0.02). The mean values in the group of pretreated animals were: kel 0.00457 min.-1, beta 0.00296 min.-1, clearance 2.04 ml kg-1 min.-1, Vd beta 693 ml kg-1. By way of comparison, the values obtained in non-pretreated guinea pigs were: kel 0.00293 min.-1 beta 0.00198 min.-1, clearance 1.50 ml kg-1 min.-1, Vd beta 757 ml kg-1. This result suggests enzyme induction to occur. The pharmacologically active theophylline metabolite 3-methylxanthine did not accumulate in the plasma during the long-term theophylline administration. The general plasma concentration level was 0-1.8 . 10(-8) mol ml-1 (0-3 microgram ml-1). In 5 per cent of the samples were detected concentrations in the range 1.8 . 10(-8) mol ml-1 (3-12 microgram ml-1), but the time of occurrence was sporadic.