Payan J P, Marty J P, Fabry J P, Beydon D, Boudry I, Ferrari E, Canel F, Grandclaude M C, Vincent C M
Institut National de Recherche et de Sécurité (INRS), Vandoeuvre, France.
Drug Metab Dispos. 2001 Jun;29(6):843-54.
This study evaluated the toxicokinetics of [(14)C]di-n-butylphthalate ([(14)C]DBP) after an intravenous administration (1 and 10 mg/kg, in Cremophor) or a topical application (10 microl/cm(2); 10 cm(2), neat) in haired male Sprague-Dawley rats. Additional in vivo and in vitro percutaneous penetration studies of [(14)C]DBP were conducted on male and female haired rats and male hairless rats. After intravenous administration, unchanged DBP disappeared rapidly from the plasma, following a two-exponential function (T1/2beta = 5-7 min). The peak levels of monobutylphthalate (MBP) and its glucuronide conjugate (MBP-Gluc) occurred 1 to 2 and 20 to 30 min after administration, respectively. These metabolites were intensively and rapidly excreted in urine (57% of the dose). However, about 35% of the dose recovered in urine was primarily excreted in bile (mainly as MBP-Gluc) and underwent hepatobiliary recycling. Unchanged DBP was barely detectable in excreta. DBP rapidly penetrated the skin, which constituted a reservoir. The absorption flux determined for 0.5 to 8 and 8 to 48 h of exposure were 43 and 156 microg/cm(2)/h, respectively. The higher flux may be due to radial diffusion of DBP in the stratum and/or epidermis. The in vivo and in vitro experiments revealed that DBP was intensively metabolized into the skin. In vivo percutaneous absorption flux was very similar in male and female haired rats. In contrast, the percutaneous absorption determined in vivo and in vitro was higher in hairless than in haired male rats. Absorption flux was accurately estimated from urinary excretion rate of MBP or MBP-Gluc.
本研究评估了在有毛雄性斯普拉格-道利大鼠中，静脉注射（1和10 mg/kg，溶于聚氧乙烯蓖麻油）或局部涂抹（10 μl/cm²；10 cm²，纯品）[(14)C]邻苯二甲酸二正丁酯([(14)C]DBP)后的毒代动力学。还对有毛雄性和雌性大鼠以及雄性无毛大鼠进行了[(14)C]DBP的额外体内和体外经皮渗透研究。静脉注射后，未代谢的DBP从血浆中迅速消失，符合双指数函数（T1/2β = 5 - 7分钟）。单丁基邻苯二甲酸酯（MBP）及其葡萄糖醛酸结合物（MBP - Gluc）的峰值水平分别在给药后1至2分钟和20至30分钟出现。这些代谢物在尿液中大量且迅速排泄（占剂量的57%）。然而，尿液中回收的约35%的剂量主要通过胆汁排泄（主要为MBP - Gluc）并经历肝胆循环。排泄物中几乎检测不到未代谢的DBP。DBP迅速渗透皮肤，皮肤成为一个储存库。暴露0.5至8小时和8至48小时测定的吸收通量分别为43和156 μg/cm²/h。较高的通量可能是由于DBP在角质层和/或表皮中的径向扩散。体内和体外实验表明，DBP在皮肤中大量代谢。有毛雄性和雌性大鼠的体内经皮吸收通量非常相似。相比之下，无毛雄性大鼠体内和体外测定的经皮吸收高于有毛雄性大鼠。吸收通量可根据MBP或MBP - Gluc的尿排泄率准确估算。
