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Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706
Author(s) -
Koizumi Fumiaki,
Murakami Manabu,
Kageyama Hiromitsu,
Katashima Masataka,
Terakawa Masato,
Ohnishi Akihiro
Publication year - 1999
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(99)70013-5
Subject(s) - cmax , pharmacokinetics , medicine , absorption (acoustics) , elimination rate constant , pharmacology , chemistry , endocrinology , volume of distribution , physics , acoustics
Purpose We compared the pharmacokinetics of the inhaled novel neutrophil elastase inhibitor FK706 between healthy nonsmokers and smokers. Methods 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. Results The plasma concentration–time curve of inhaled FK706 was apparently different between smokers and nonsmokers. The maximum plasma concentrations (C max ) 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 C max (t max ) and elimination half‐life (t ½ ) were statistically smaller in the smokers compared with the t max and elimination t ½ in the nonsmokers (t max in smokers, 0.44 ± 0.27 hours; t max in nonsmokers, 1.17 ± 0.39 hours [ P < .01]; t ½ in smokers, 1.23 ± 0.40 hours; t ½ 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 (k a ) was about 10 times greater in smokers than the k a in nonsmokers. Conclusion Significant increases of C max and k a and reductions of t max and elimination t ½ 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. Clinical Pharmacology & Therapeutics (1999) 66 , 501–508; doi: