Mathews J M, deCosta K, Thomas B F
Center for Bioorganic Chemistry, Research Triangle Institute, RTP, NC 27709, USA.
Drug Metab Dispos. 1996 Jul;24(7):702-10.
The disposition of carbon-14-labeled lauramide diethanolamine (LDEA) was determined in rats after iv, dermal, and oral administration, and in mice after iv and dermal administration. Intravenous doses of LDEA to rats and mice (25 and 50 mg/kg, respectively) were mostly excreted in the urine (ca. 80-90%), with only about 10% excreted in the feces 72 hr after dosing. No unchanged LDEA, diethanolamine, or diethanolamine-derived metabolites were detected in urine. LDEA concentrated to the highest levels in the adipose tissue, and was only very slowly cleared from that tissue. Residues were also observed in liver and kidney, but clearance from those tissues paralleled the decreases in blood concentrations. Incubations of LDEA with liver slices from rats and humans showed that the compound is well absorbed by hepatic tissue from both species. LDEA was readily converted to metabolites found in vivo in rats, as well as other metabolites that are potentially intermediate products formed after omega- and/or omega-1 to 4 hydroxylation. Treatment with diethylhexylphthalate, an inducer of cytochrome P4504A1, which catalyzes the omega-hydroxylation of lauric and other fatty acids, demonstrated the involvement of that isozyme in the hydroxylation of LDEA. Dermally applied LDEA, at doses of 25 and 400 mg/kg to rats, was moderately (25-30%) well absorbed. Repeat administration (25 mg/kg/day for 3 weeks) did not change the rate of LDEA absorption. The absorption of 100 mg/kg doses was studied in jugular vein-cannulated rats. Steady state levels of LDEA equivalents were reached 24 hr after dermal administration. LDEA comprised about 15% of the radioactivity in plasma, with the remainder present as polar metabolites. A range of 50-70% of the dermal doses to mice, applied at 50, 100, 200, and 800 mg/kg, was absorbed in 72 hr. Absorbed LDEA distributed into the tissues with the same relative profile as that for the iv dose, except that distribution into adipose tissue was considerably lower. High oral doses of LDEA (100 mg/kg) in rats were well absorbed and mostly excreted in the urine as two very polar metabolites. The metabolites were isolated and characterized as the half-acid amides of succinic and of adipic acid, presumably arising from omega-hydroxylation and eventual beta-oxidation to give the chain-shortened products.
在大鼠经静脉注射、皮肤给药和口服给药后，以及在小鼠经静脉注射和皮肤给药后，测定了碳 - 14标记的月桂酰胺二乙醇胺（LDEA）的处置情况。给大鼠和小鼠静脉注射的LDEA剂量分别为25和50 mg/kg，给药72小时后，大部分经尿液排泄（约80 - 90%），只有约10%经粪便排泄。在尿液中未检测到未变化的LDEA、二乙醇胺或二乙醇胺衍生的代谢物。LDEA在脂肪组织中浓度最高，且从该组织中清除非常缓慢。在肝脏和肾脏中也观察到残留，但这些组织中的清除与血液浓度的降低平行。LDEA与大鼠和人类肝脏切片的孵育表明，该化合物在两种物种的肝组织中均能被很好地吸收。LDEA很容易转化为大鼠体内发现的代谢物，以及其他可能是ω - 和/或ω - 1至4羟基化后形成的中间产物的代谢物。用邻苯二甲酸二己酯（一种细胞色素P4504A1的诱导剂，可催化月桂酸和其他脂肪酸的ω - 羟基化）处理表明，该同工酶参与了LDEA的羟基化。给大鼠皮肤涂抹25和400 mg/kg剂量的LDEA，吸收适中（25 - 30%）。重复给药（25 mg/kg/天，共3周）并未改变LDEA的吸收速率。在颈静脉插管的大鼠中研究了100 mg/kg剂量的吸收情况。皮肤给药24小时后达到LDEA等效物的稳态水平。LDEA约占血浆放射性的15%，其余以极性代谢物形式存在。给小鼠分别以50、100、200和800 mg/kg的剂量经皮肤涂抹LDEA，72小时内吸收范围为50 - 70%。吸收的LDEA分布到组织中的相对情况与静脉注射剂量相同，只是在脂肪组织中的分布明显较低。给大鼠口服高剂量的LDEA（100 mg/kg）吸收良好，大部分以两种极性很强的代谢物形式经尿液排泄。这些代谢物被分离并鉴定为琥珀酸和己二酸的半酸酰胺，推测是由ω - 羟基化和最终的β - 氧化产生链缩短产物而形成的。
