Poor and enantioselective bioavailability of naftopidil enantiomers is due to extensive and stereoselective metabolism in rat liver
Poor and enantioselective bioavailability of naftopidil enantiomers is due to extensive and stereoselective metabolism in rat liver
复制标题
萘哌地尔对映异构体的低对映选择性生物利用度是由于大鼠肝脏中广泛的立体选择性代谢所致
DOI：
10.1016/j.jpba.2016.09.038
复制
发表时间：
2017-01-05
影响因子：
3.4
通讯作者：
Yuan, Mu
中科院分区：
文献类型：
--
作者：
Liu, Xiawen;Zhu, Lijun;Yuan, Mu
外消旋萘哌地尔（NAF）用于治疗良性前列腺增生（BPH）和前列腺癌（PCa）。它表现出更大的疗效，但需要更高的剂量比其他α 1-肾上腺素受体阻滞剂，因为它的生物利用度差。此前已有研究表明，S（-）-NAF的生物利用度（14.5%）是R（+）-NAF（6.8%）的两倍。本研究旨在阐明NAF生物利用度差和对映体选择性差的主要因素。首先，使用灌流肠模型检查NAF对映体的吸收。发现NAF对映体在肠的所有节段中具有相等的高度渗透性。其次，研究了在肠的不同部分和胆汁中形成的代谢物。NAF对映体的葡萄糖醛酸化主要发生在肝脏中。第三，采用超高效液相色谱-三重四极杆质谱联用（UPLC-MS/MS）法定量计算大鼠静脉注射NAF对映体及其葡萄糖醛酸苷后的药代动力学参数。R（+）-NAF葡萄糖醛酸苷（R（+）-NAF-G）和S（-）-NAF葡萄糖醛酸苷（S（-）-NAF-G）的含量分别是R（+）-NAF的6倍和S（-）-NAF的3倍。S（-）NAF的葡萄糖醛酸化速度比R（+）-NAF快，但结合量只有R（+）-NAF的一半。因此，S（-）-NAF的生物利用度是R（+）-NAF的两倍。总之，肝脏中广泛的II相代谢显著导致NAF对映体的低生物利用度。葡萄糖醛酸化是NAF对映体最重要的代谢途径。S（-）-NAF的葡萄糖醛酸化比R（+）-NAF更快，但程度较低。(C)© 2016 Elsevier B. V.版权所有。
Racemic naftopidil (NAF) is used to treat benign prostatic hyperplasia (BPH) and prostatic cancer (PCa). It exhibits greater efficacy but requires higher dose than other alpha 1-adrenoceptor blockers because of its poor bioavailability. It was previously shown that bioavailability of S(-)-NAF (14.5%) was twice that of R(+)-NAF (6.8%). The present study aimed to elucidate the major factors contributing to the poor and enantioselective bioavailability of NAF. First, absorption of NAF enantiomers was examined using a perfusated intestinal model. NAF enantiomers were found to be equally and highly permeable in all segments of the intestine. Second, the metabolites formed in different parts of the intestine and in bile were investigated. Glucuronidation of NAF enantiomers was found to occur primarily in the liver. Third, a new method consisting of ultra performance liquid chromatography coupled with triple-quadruple mass spectrometry (UPLC-MS/MS) was employed to quantify and calculate the pharmacokinetic parameters of NAF enantiomers and their glucuronides after the enantiomers were intravenously injected into rats. The amounts of R(+)-NAF glucuronide (R(+)-NAF-G) and S(-)-NAF glucuronide (S(-)-NAF-G) were six-fold higher than that of R(+)-NAF, and three-fold higher than that of S(-)-NAF. Glucuronidation of S(-)NAF was faster than that of R(+)-NAF, but the conjugated amount was half of that of R(+)-NAF. Thus, bioavailability of S(-)-NAF was twice that of R(+)-NAF. In conclusion, extensive phase II metabolism in the liver significantly contributes to the low bioavailability of NAF enantiomers. Glucuronidation is the most important metabolic pathway for NAF enantiomers. Glucuronidation of S(-)-NAF is faster but occurs to a lesser extent than that of R(+)-NAF. (C) 2016 Elsevier B.V. All rights reserved.