Goosen Theunis C, Bauman Jonathan N, Davis John A, Yu Chongwoo, Hurst Susan I, Williams J Andrew, Loi Cho-Ming
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Rd., Ann Arbor, MI 48105, USA.
Drug Metab Dispos. 2007 Aug;35(8):1315-24. doi: 10.1124/dmd.107.015230. Epub 2007 Apr 30.
Gemfibrozil coadministration generally results in plasma statin area under the curve (AUC) increases, ranging from moderate (2- to 3-fold) with simvastatin, lovastatin, and pravastatin to most significant with cerivastatin (5.6-fold). Inhibition of statin glucuronidation has been postulated as a potential mechanism of interaction (Drug Metab Dispos 30:1280-1287, 2002). This study was conducted to determine the in vitro inhibitory potential of fibrates toward atorvastatin glucuronidation. [(3)H]Atorvastatin, atorvastatin, and atorvastatin lactone were incubated with human liver microsomes or human recombinant UDP-glucuronosyltransferases (UGTs) and characterized using liquid chromatography (LC)/tandem mass spectrometry and LC/UV/beta-radioactivity monitor/mass spectrometry. [(3)H]Atorvastatin yields a minor ether glucuronide (G1) and a major acyl glucuronide (G2) with subsequent pH-dependent lactonization of G2 to yield atorvastatin lactone. Atorvastatin lactonization best fit substrate inhibition kinetics (K(m) = 12 microM, V(max) = 74 pmol/min/mg, K(i) = 75 microM). Atorvastatin lactone yields a single ether glucuronide (G3). G3 formation best fit Michaelis-Menten kinetics (K(m) = 2.6 microM, V(max) = 10.6 pmol/min/mg). Six UGT enzymes contribute to atorvastatin glucuronidation with G2 and G3 formation catalyzed by UGTs 1A1, 1A3, 1A4, 1A8, and 2B7, whereas G1 formation was catalyzed by UGTs 1A3, 1A4, and 1A9. Gemfibrozil, fenofibrate, and fenofibric acid inhibited atorvastatin lactonization with IC(50) values of 346, 320, and 291 microM, respectively. Based on unbound fibrate concentrations at the inlet to the liver, these data predict a small increase in atorvastatin AUC (approximately 1.2-fold) after gemfibrozil coadministration and no interaction with fenofibrate. This result is consistent with recent clinical reports indicating minimal atorvastatin AUC increases ( approximately 1.2- to 1.4-fold) with gemfibrozil.
吉非贝齐联合用药通常会导致血浆中他汀类药物的曲线下面积（AUC）增加，范围从中度增加（辛伐他汀、洛伐他汀和普伐他汀增加2至3倍）到与西立伐他汀联合使用时增加最为显著（5.6倍）。他汀类药物葡萄糖醛酸化的抑制作用被认为是一种潜在的相互作用机制（《药物代谢与处置》30:1280 - 1287, 2002）。本研究旨在确定贝特类药物对阿托伐他汀葡萄糖醛酸化的体外抑制潜力。将[³H]阿托伐他汀、阿托伐他汀和阿托伐他汀内酯与人肝微粒体或人重组尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）一起孵育，并使用液相色谱（LC）/串联质谱以及LC/紫外/β放射性监测器/质谱进行表征。[³H]阿托伐他汀产生一种次要的醚葡萄糖醛酸化物（G1）和一种主要的酰基葡萄糖醛酸化物（G2），随后G2发生pH依赖性内酯化生成阿托伐他汀内酯。阿托伐他汀内酯化最符合底物抑制动力学（米氏常数K(m)=12微摩尔，最大反应速度V(max)=74皮摩尔/分钟/毫克，抑制常数K(i)=75微摩尔）。阿托伐他汀内酯产生单一的醚葡萄糖醛酸化物（G3）。G3的形成最符合米氏动力学（K(m)=2.6微摩尔，V(max)=10.6皮摩尔/分钟/毫克）。六种UGT酶参与阿托伐他汀的葡萄糖醛酸化，UGT 1A1、1A3、1A4、1A8和2B7催化G2和G3的形成，而UGT 1A3、1A4和1A9催化G1的形成。吉非贝齐、非诺贝特和非诺贝酸抑制阿托伐他汀内酯化，其半数抑制浓度（IC(50)）值分别为346、320和291微摩尔。根据肝脏入口处未结合的贝特类药物浓度，这些数据预测吉非贝齐联合用药后阿托伐他汀的AUC会有小幅增加（约1.2倍），且与非诺贝特无相互作用。这一结果与近期临床报告一致，即吉非贝齐联合使用时阿托伐他汀的AUC增加幅度最小（约1.2至1.4倍）。
