Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706

Purpose: We compared the pharmacokinetics of the inhaled novel neutrophil e lastase 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 co mpared after standardization by doses. Results: The plasma concentration-time curve of inhaled FK706 was apparentl y different between smokers and nonsmokers. The maximum plasma concentratio ns (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-li fe (t(1/2)) were statistically smaller in the smokers compared with the t(m ax) and elimination t(1/2) in the nonsmokers (t(1/2) in smokers, 0.44 +/- 0 .27 hours; t(max) in nonsmokers, 1.17 +/- 0.39 hours [P < .01]; t(1/2) in s mokers, 1.23 +/- 0.40 hours; t(1/2) in nonsmokers, 2.73 +/- 0.57 hours [P < .01]). The area under the plasma concentration-time curve and plasma clear ance were not significantly different between the two groups. Model-depende nt 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(1/2) 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 ha s a narrow therapeutic range.