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标题：TIME-DEPENDENT PHARMACOKINETICS OF THEOPHYLLINE : FAILURE OF APPLICATION OF THE TEST-DOSE CONCEPT
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作者：MITSUYOSHI GOTO ; IKUO JOHNO ; MASAYA HASEGAWA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1987
卷号：10
期号：10
页码：543-549
DOI：10.1248/bpb1978.10.543
出版社：The Pharmaceutical Society of Japan
摘要：A comparative pharmacokinetic study of theophylline between the first and repeated oral administration and the assessment of clinical utility of theophylline test-dose concept were performed in 6 (study I) and 4 (study II) healthy male volunteers with different dosing schedules. In study I, although the average of theophylline systemic clearance (Cl_sys) was significantly (p<0.05) lower in the repeated dosing than in the first dosing, large intersubject variations were observed. Plasma free fatty acids which inhibit drug metabolizing enzyme activity were not influenced by theophylline chronic administration. In study II, the volunteers received oral multiple doses of a theophylline powder preparation to maintain 5 to 15 μg/ml plasma concentration on the basis of the pharmacokinetic parameters calculated from the single oral test-dose. A good prediction of the plasma concentration was observed only in one case and the maximum levels in the rest exceeded 20 μg/ml, a toxic concentration. Throughout the Studies, a stable Cl_sys was obtained in smokers, but the Cl_sys in non-smokers decreased by one third to a half during multiple dosing. These findings suggest that theophylline showed time-dependent pharmacokinetics and that test-dose concept for theophylline may not be applicable in all cases because of a large intersubject variation in the Cl_sys change between single and multiple dosing.
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