Tocco D J, Duncan A E, deLuna F A, Wells G
Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Drug Metab Dispos. 1988 Sep-Oct;16(5):697-700.
14C-labeled 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)-sulfonyl]-gamma- oxobenzenebutanoate (L-648,051) was suspended in Freon under pressure and injected into rat lungs via a tracheal cannula. The particle size of the drug was 1 to 5 microns and the mean dose was approximately 0.2 mg/kg. Levels of radioactivity in the lung/trachea declined in a monoexponential manner. Absorption, estimated from radioactivity remaining in the lung and trachea, was 73% in 1 hr and 95% in 4 hr. L-648,051 and its pharmacologically active metabolite L-657,098 (formed by ketoreduction of the butanoic acid moiety of L-648,051) accounted for 96% of the radioactivity in the lung at 10 min after the dose and 91% after 60 min. The lung:plasma concentration ratio of active drug (L-648,051 plus L-657,098) was at least 176:1 at 10 min and 17:1 at 60 min (compared with 1:1 after 2 mg/kg iv) suggesting that aerosol administration of L-648,051 in humans may result in an ideal therapeutic ratio, with high levels of pharmacologically active ingredient in the lung and low levels in the plasma.
将14C标记的4-[(3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基)-磺酰基]-γ-氧代苯丁酸酯（L-648,051）在压力下悬浮于氟利昂中，并通过气管插管注入大鼠肺部。药物的粒径为1至5微米，平均剂量约为0.2mg/kg。肺/气管中的放射性水平呈单指数下降。根据肺和气管中残留的放射性估计，1小时内的吸收率为73%，4小时内为95%。给药后10分钟，L-648,051及其药理活性代谢物L-657,098（由L-648,051的丁酸部分酮还原形成）占肺中放射性的96%，60分钟后占91%。活性药物（L-648,051加L-657,098）的肺：血浆浓度比在10分钟时至少为176:1，60分钟时为17:1（相比2mg/kg静脉注射后为1:1），这表明在人类中雾化给药L-648,051可能会产生理想的治疗比率，即肺中具有高浓度的药理活性成分而血浆中浓度较低。
