Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706.
OBJECTIVE
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 (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.


CONCLUSIONS
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.
Koizumi
F
F
Department of Internal Medicine, Daisan Hospital, Jikei University School of Medicine, Komae, Tokyo, Japan.
Murakami
M
M
Kageyama
H
H
Katashima
M
M
Terakawa
M
M
Ohnishi
A
A
D000328:Adult; D019540:Area Under Curve; D001565:Benzoates / Q000097:blood*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007408:Intestinal Absorption; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008297:Male; D011759:Pyrrolidines / Q000097:blood*; D012016:Reference Values; D012907:Smoking / Q000097:blood*; D013997:Time Factors
D001565:Benzoates; C109799:FK 706; D011759:Pyrrolidines; D019272:Leukocyte Elastase