Mihara K, Matsumura M, Yoshioka E, Hanada K, Nakasa H, Ohmori S, Kitada M, Ogata H
Department of Biopharmaceutics, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
Pharm Res. 2001 Aug;18(8):1131-7. doi: 10.1023/a:1010922925928.
The purpose of this study was to clarify quantitatively the contribution of the intestine to the first-pass metabolism of eperisone in rats.
The systemic availabilities of eperisone were estimated by administering the drug into the duodenum, portal vein, and femoral vein in rats in vivo. The first-pass metabolism of eperisone was confirmed in the perfused rat small intestine in situ. Metabolism of eperisone to an omega-1-hydroxylated metabolite (HMO), the first step of eperisone metabolism, was studied using rat intestinal microsomes in vitro.
The bioavailabilities in the intestine were 0.176 and 0.0879 at administration rates of 100 and 25 mg/h/kg, respectively, whereas those in the liver were 0.532 and 0.486, respectively. In the intestinal perfusion experiment, the appearance clearance to the portal vein from the intestinal lumen was much lower than the elimination clearance from the intestinal lumen, resulting in high metabolic clearance of eperisone in the small intestine. Eperisone was biotransformed to HMO by rat intestinal microsomes, and this was inhibited by alpha-naphthoflavone and an anti-rat CYP1A antibody.
Those data strongly suggest that eperisone may be metabolized to HMO by CYP1A in rat intestinal microsomes during the first-pass through the epithelium of the small intestine.
本研究旨在定量阐明肠道对大鼠中乙哌立松首过代谢的贡献。
通过在大鼠体内将药物注入十二指肠、门静脉和股静脉来估算乙哌立松的全身可用性。在原位灌注的大鼠小肠中证实了乙哌立松的首过代谢。使用大鼠肠道微粒体在体外研究了乙哌立松代谢为ω-1-羟基化代谢物（HMO）这一首过代谢的第一步。
在给药速率为100和25mg/h/kg时，肠道中的生物利用度分别为0.176和0.0879，而肝脏中的生物利用度分别为0.532和0.486。在肠道灌注实验中，从肠腔到门静脉的外观清除率远低于从肠腔的消除清除率，导致乙哌立松在小肠中的代谢清除率很高。乙哌立松被大鼠肠道微粒体生物转化为HMO，并且这被α-萘黄酮和抗大鼠CYP1A抗体所抑制。
这些数据有力地表明，乙哌立松在首次通过小肠上皮时可能在大鼠肠道微粒体中被CYP1A代谢为HMO。
