Koizumi F, Murakami M, Kageyama H, Katashima M, Terakawa M, Ohnishi A
Department of Internal Medicine, Daisan Hospital, Jikei University School of Medicine, Komae, Tokyo, Japan.
Clin Pharmacol Ther. 1999 Nov;66(5):501-8. doi: 10.1016/S0009-9236(99)70013-5.
We compared the pharmacokinetics of the inhaled novel neutrophil elastase inhibitor FK706 between healthy nonsmokers and smokers.
Six healthy nonsmokers and six smokers inhaled 50 to 400 mg FK706 in two different doses. Series of plasma concentrations of the SSS form of FK706 (pharmacologically active epimer) were analyzed model dependently and independently. Pharmacokinetic parameters obtained from each group were compared after standardization by doses.
The plasma concentration-time curve of inhaled FK706 was apparently different between smokers and nonsmokers. The maximum plasma concentrations (Cmax) were significantly higher in the smokers than in the nonsmokers (smokers, 1.47 +/- 0.62 ng/mL/mg; nonsmokers, 0.49 +/- 0.14 ng/mL/mg [mean +/- SD; P < .01]). The time to reach Cmax (tmax) and elimination half-life (t1/2) were statistically smaller in the smokers compared with the tmax and elimination t1/2 in the nonsmokers (tmax in smokers, 0.44 +/- 0.27 hours; tmax in nonsmokers, 1.17 +/- 0.39 hours [P < .01]; t1/2 in smokers, 1.23 +/- 0.40 hours; t1/2 in nonsmokers, 2.73 +/- 0.57 hours [P < .01]). The area under the plasma concentration-time curve and plasma clearance were not significantly different between the two groups. Model-dependent pharmacokinetic analysis, assuming a flip-flop model, revealed that the absorption rate constant (ka) was about 10 times greater in smokers than the ka in nonsmokers.
Significant increases of Cmax and ka and reductions of tmax and elimination t1/2 of the inhaled FK706 were observed in the healthy smokers, suggesting that the smoking habit accelerates the drug absorption after inhalation. These results suggest that we should pay attention to the drug-related adverse events caused by smoking, especially when the drug has a narrow therapeutic range.
我们比较了吸入新型中性粒细胞弹性蛋白酶抑制剂FK706在健康非吸烟者和吸烟者中的药代动力学。
6名健康非吸烟者和6名吸烟者以两种不同剂量吸入50至400毫克FK706。对FK706的SSS形式（具有药理活性的差向异构体）的一系列血浆浓度进行了模型依赖性和非依赖性分析。对每组获得的药代动力学参数按剂量标准化后进行比较。
吸烟者和非吸烟者吸入FK706后的血浆浓度-时间曲线明显不同。吸烟者的最大血浆浓度（Cmax）显著高于非吸烟者（吸烟者，1.47±0.62纳克/毫升/毫克；非吸烟者，0.49±0.14纳克/毫升/毫克[平均值±标准差；P<.01]）。与非吸烟者相比，吸烟者达到Cmax的时间（tmax）和消除半衰期（t1/2）在统计学上更小（吸烟者的tmax，0.44±0.27小时；非吸烟者的tmax，1.17±0.39小时[P<.01]；吸烟者的t1/2，1.23±0.40小时；非吸烟者的t1/2，2.73±0.57小时[P<.01]）。两组之间的血浆浓度-时间曲线下面积和血浆清除率无显著差异。假设为翻转模型的模型依赖性药代动力学分析显示，吸烟者的吸收速率常数（ka）比非吸烟者的ka大约高10倍。
在健康吸烟者中观察到吸入FK706的Cmax和ka显著增加，tmax和消除t1/2降低，这表明吸烟习惯会加速吸入后药物的吸收。这些结果表明，我们应该注意吸烟引起的与药物相关的不良事件，尤其是当药物的治疗范围较窄时。
