The Pharmacokinetics and Bioavailability of Clemastine and Phenylpropanolamine in Single-Component and Combination Formulations

药代动力学 生物利用度 苯丙醇胺 生物等效性 药理学 交叉研究 最大值 分配量 化学 口服 医学 安慰剂 病理 替代医学
作者
Horst Schran,Lew Petryk,Cheng‐Tao Chang,Robert O’Connor,Mark B. Gelbert
出处
期刊:The Journal of Clinical Pharmacology [Wiley]
卷期号:36 (10): 911-922 被引量:25
标识
DOI:10.1002/j.1552-4604.1996.tb04758.x
摘要

Studies were conducted in healthy male volunteers (n = 171; age range, 19–49 years; 22–27 subjects per study) to examine the following: pharmacokinetics and dose proportionality of the antihistamine clemastine; the effect of coadministration of phenylpropanolamine and clemastine on the pharmacokinetics of the two drugs; and the bioavailability of clemastine tablets and combination tablets of clemastine and sustained‐release phenylpropanolamine under fasted and fed conditions after single‐dose administration and at steady state. All studies used crossover designs, with randomized drug treatments separated by a 7‐day washout period for the single‐dose studies, and with administration every 6 or 12 hours for 7 days per treatment for the steady‐state studies. After single oral doses of clemastine solution (1, 2, and 4 mg), the area under the concentration—time curve (AUC) and maximum concentration (C max ) were dose proportional. Clemastine showed a first‐pass reduction in the extent of absorption, with oral bioavailability calculated as 39.2 ± 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 ± 315 L) and low C max (0.577 ± 0.252 ng/mL/mg) observed at 4.77 ± 2.26 hours after administration, and by the biphasic decline in plasma concentration. The terminal elimination half‐life (t 1/2 ) of clemastine was 21.3 ± 11.6 hours. Steady‐state concentrations of clemastine were consistent with linear pharmacokinetic processes, and clearance was unaffected by age in the range studied, or by race. Clemastine solution and tablets were bioequivalent, and food had no significant effect on rate and extent of absorption of clemastine. The 1‐ and 2‐mg clemastine tablets showed proportional bioavailability. Coadministration of clemastine with phenylpropanolamine did not significantly influence the pharmacokinetics of clemastine or the AUC and elimination t 1/2 of phenylpropanolamine, but reduced the rate of absorption of phenylpropanolamine. Combination tablets containing 1 mg or 2 mg of immediate‐release clemastine plus 75 mg of sustained‐release phenylpropanolamine for twice daily administration were bioequivalent to the separate components and showed no significant interaction with food.
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