Prueksaritanont Thomayant, Qiu Yue, Mu Lillian, Michel Kimberly, Brunner Janice, Richards Karen M, Lin Jiunn H
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Pharm Res. 2005 Jul;22(7):1101-9. doi: 10.1007/s11095-005-6037-2. Epub 2005 Jul 22.
To characterize the pharmacokinetics of simvastatin (SV) and simvastatin acid (SVA), a lactone-acid pair known to undergo reversible metabolism, and to better understand mechanisms underlying pharmacokinetic interactions observed between SV and gemfibrozil.
Pharmacokinetic studies were conducted after intravenous administration of SV and SVA to dogs pretreated with a vehicle or gemfibrozil. In vitro metabolism of SVA in dog hepatocytes as well as in vitro hepatic and plasma conversion of SV/SVA were investigated in the absence and presence of gemfibrozil.
In control animals, the irreversible elimination clearances of SV (CL10) and SVA (CL20) were 10.5 and 18.6 ml min(-1) kg(-1), respectively. The formation clearance of SVA from SV (CL12 = 4.8 ml min(-1) kg(-1)) was 8-fold greater than that of SV from SVA (CL21 = 0.6 ml min(-1) kg(-1)), and the recycled fraction was relatively minor (0.009). In gemfibrozil-treated animals, CL10 was essentially unchanged, whereas CL12, CL20, CL21, and recycled fraction were significantly decreased to 2.9, 9, 0.14 ml min(-1) kg(-1), and 0.003, respectively. In control dogs, values for real volume of distribution at steady state (Vss,real) of SV (2.3 L kg(-1)) were much larger than the corresponding values of SVA (0.3 L kg(-1)). Gemfibrozil treatment did not affect Vss,real of either SV or SVA. In dog hepatocytes, gemfibrozil modestly affected the formation of CYP3A-mediated oxidative metabolites (IC50 > 200 microM) and beta-oxidative products (IC5) approximately 100 microM), but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of an SVA beta-oxidation product (IC50 = 18 microM). In in vitro dog and human liver S9 and plasma, hydrolysis of SV to SVA was much faster than that of SVA to SV. Gemfibrozil (250 microM) had a minimal inhibitory effect on the hydrolysis of either SV to SVA or SVA to SV in dog and human liver S9, but had a significant ( approximately 60%) inhibitory effect on the SV to SVA hydrolysis in both dog and human plasma.
In dogs, the interconversion process favored the formation of SVA and was less efficient than the irreversible elimination processes of SV and SVA. Treatment with gemfibrozil did not affect the distribution of SV/SVA, but rather affected the elimination of SVA and the SV/SVA interconversion processes. Gemfibrozil decreased CL20 and CL21 likely via its inhibitory effect on the glucuronidation of SVA, and not on the CYP3A-mediated oxidative metabolism of SV or SVA, the beta-oxidation of SVA, nor the SVA to SV hydrolysis. The decrease in CL12 might be due in part to the inhibitory effect of gemfibrozil on SV to SVA hydrolysis in plasma. Similar rationales may also be applicable to studies in humans and/or other statin lactone-acid pairs.
表征辛伐他汀（SV）和辛伐他汀酸（SVA）的药代动力学，这是一对已知会进行可逆代谢的内酯 - 酸对，并更好地理解在SV与吉非贝齐之间观察到的药代动力学相互作用的潜在机制。
对用载体或吉非贝齐预处理的犬静脉注射SV和SVA后进行药代动力学研究。在不存在和存在吉非贝齐的情况下，研究了犬肝细胞中SVA的体外代谢以及SV/SVA的体外肝脏和血浆转化。
在对照动物中，SV（CL10）和SVA（CL20）的不可逆消除清除率分别为10.5和18.6 ml·min⁻¹·kg⁻¹。从SV生成SVA的生成清除率（CL12 = 4.8 ml·min⁻¹·kg⁻¹）比从SVA生成SV的生成清除率（CL21 = 0.6 ml·min⁻¹·kg⁻¹）大8倍，且循环分数相对较小（0.009）。在吉非贝齐治疗的动物中，CL10基本不变，而CL12、CL20、CL21和循环分数分别显著降低至2.9、9、0.14 ml·min⁻¹·kg⁻¹和0.003。在对照犬中，SV的稳态真实分布容积（Vss,real）值（2.3 L·kg⁻¹）远大于SVA的相应值（0.3 L·kg⁻¹）。吉非贝齐治疗不影响SV或SVA的Vss,real。在犬肝细胞中，吉非贝齐对CYP3A介导的氧化代谢产物（IC50 > 200 μM）和β - 氧化产物（IC5约为100 μM）的形成有适度影响，但显著抑制SVA的葡萄糖醛酸化介导的内酯化以及SVAβ - 氧化产物的葡萄糖醛酸化（IC50 = 18 μM）。在体外犬和人肝脏S9以及血浆中，SV水解为SVA的速度比SVA水解为SV的速度快得多。吉非贝齐（250 μM）对犬和人肝脏S9中SV水解为SVA或SVA水解为SV的抑制作用最小，但对犬和人血浆中SV水解为SVA有显著（约60%）抑制作用。
在犬中，相互转化过程有利于SVA的形成，且效率低于SV和SVA的不可逆消除过程。吉非贝齐治疗不影响SV/SVA的分布，但影响SVA的消除以及SV/SVA相互转化过程。吉非贝齐可能通过对SVA葡萄糖醛酸化的抑制作用降低CL20和CL21，而不是对SV或SVA的CYP3A介导的氧化代谢、SVA的β - 氧化或SVA水解为SV的过程产生抑制作用。CL12的降低可能部分归因于吉非贝齐对血浆中SV水解为SVA的抑制作用。类似的原理也可能适用于人类研究和/或其他他汀类内酯 - 酸对的研究。
