Tocco D J, deLuna F A, Duncan A E, Ramjit H G, Pitzenberger S M, Hsieh J Y
Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Drug Metab Dispos. 1988 Sep-Oct;16(5):690-6.
The disposition of sodium 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma-o xo benzenebutanoate (L-648,051) was determined in rats and dogs. L-648,051 is a potent receptor antagonist for leukotriene D4 and is potentially useful in the treatment of asthma and other allergic disorders. After a dosage of 10 mg/kg iv, L-648,051 declined rapidly with a half-life of approximately 2 min in rat and dog plasma. Although the compound was well absorbed, it exhibited poor bioavailability due to efficient first-pass metabolism. In rats receiving 25, 50, and 150 mg/kg po, bioavailabilities were 0.5, 4.8, and 38.7%, respectively. In dogs, bioavailability of 10 and 50 mg/kg po was 0 and 23%, respectively. Two metabolites were identified, 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl-gamma- hydroxybenzenebutanoic acid (metabolite I), formed by ketoreduction, and 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl] benzeneacetic acid (metabolite II) formed by catabolic oxidation of the butanoic acid moiety of L-648,051. Ketoreduction resulted in the production of a chiral center and two enantiomers of metabolite I. In vitro studies suggest that rat erythrocytes formed the (+)-enantiomer exclusively. When L-648,051 was administered orally or iv to rats, both the (+)- and (-)-enantiomers were observed in the plasma. The data suggest that either two L-648,051 ketoreductases were present or that inversion of the hydroxyl stereocenter of metabolite I occurred.
测定了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（L-648,051）在大鼠和犬体内的处置情况。L-648,051是一种强效的白三烯D4受体拮抗剂，在哮喘和其他过敏性疾病的治疗中可能具有应用价值。静脉注射10 mg/kg剂量后，L-648,051在大鼠和犬血浆中迅速下降，半衰期约为2分钟。尽管该化合物吸收良好，但由于有效的首过代谢，其生物利用度较差。在口服给予25、50和150 mg/kg的大鼠中，生物利用度分别为0.5%、4.8%和38.7%。在犬中，口服10和50 mg/kg的生物利用度分别为0和23%。鉴定出两种代谢产物，4-[(3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基)磺酰基]-γ-羟基苯丁酸（代谢产物I），由酮还原形成，以及4-[(3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基)磺酰基]苯乙酸（代谢产物II），由L-648,051的丁酸部分分解氧化形成。酮还原导致产生一个手性中心和代谢产物I的两种对映体。体外研究表明，大鼠红细胞仅形成(+)-对映体。当给大鼠口服或静脉注射L-648,051时，血浆中观察到(+)-和(-)-对映体。数据表明，要么存在两种L-648,051酮还原酶，要么代谢产物I的羟基立体中心发生了构型翻转。
