Jacobsen W, Kuhn B, Soldner A, Kirchner G, Sewing K F, Kollman P A, Benet L Z, Christians U
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California 94143-0446, USA.
Drug Metab Dispos. 2000 Nov;28(11):1369-78.
In an in vitro study, we compared the cytochrome P450 (CYP)-dependent metabolism and drug interactions of the acid and lactone forms of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor atorvastatin. Metabolism of atorvastatin acid and lactone by human liver microsomes resulted in para-hydroxy and ortho-hydroxy metabolites. Both substrates were metabolized mainly by CYP3A4 and CYP3A5. Atorvastatin lactone had a significantly higher affinity to CYP3A4 than the acid (K(m): para-hydroxy atorvastatin, 25.6 +/- 5.0 microM; para-hydroxy atorvastatin lactone, 1.4 +/- 0.2 microM; ortho-hydroxy atorvastatin, 29.7 +/- 9.4 microM; and ortho-hydroxy atorvastatin lactone, 3.9 +/- 0.2 microM). Compared with atorvastatin acid, CYP-dependent metabolism of atorvastatin lactone to its para-hydroxy metabolite was 83-fold higher [formation CL(int) (V(max)/K(m)): lactone 2949 +/- 3511 versus acid 35.5 +/- 48.1 microl. min(-1). mg(-1)] and to its ortho-hydroxy metabolite was 20-fold higher (CL(int): lactone 923 +/- 965 versus acid 45.8 +/- 59. 1 microl. min(-1). mg(-1)). Atorvastatin lactone inhibited the metabolism of atorvastatin acid by human liver microsomes with an inhibition constant (K(i)) of 0.9 microM while the K(i) for inhibition of atorvastatin by atorvastatin lactone was 90 microM. Binding free energy calculations of atorvastatin acid and atorvastatin lactone complexed with CYP3A4 revealed that the smaller desolvation energy of the neutral lactone compared with the anionic acid is the dominant contribution to the higher binding affinity of the lactone rather than an entropy advantage. Because atorvastatin lactone has a significantly higher metabolic clearance and the lactone is a strong inhibitor of atorvastatin acid metabolism, it can be expected that metabolism of the lactone is the relevant pathway for atorvastatin elimination and drug interactions. We hypothesize that most of the open acid metabolites present in human plasma are generated by interconversion of lactone metabolites.
在一项体外研究中，我们比较了3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂阿托伐他汀的酸形式和内酯形式的细胞色素P450（CYP）依赖性代谢及药物相互作用。人肝微粒体对阿托伐他汀酸和内酯的代谢产生了对羟基和邻羟基代谢物。两种底物主要由CYP3A4和CYP3A5代谢。阿托伐他汀内酯对CYP3A4的亲和力显著高于酸形式（米氏常数（K(m)）：对羟基阿托伐他汀，25.6±5.0微摩尔；对羟基阿托伐他汀内酯，1.4±0.2微摩尔；邻羟基阿托伐他汀，29.7±9.4微摩尔；邻羟基阿托伐他汀内酯，3.9±0.2微摩尔）。与阿托伐他汀酸相比，阿托伐他汀内酯经CYP依赖性代谢生成其对羟基代谢物的速率高83倍[内在清除率（CL(int)）（V(max)/K(m)）：内酯为2949±3511，而酸为35.5±48.1微升·分钟⁻¹·毫克⁻¹]，生成其邻羟基代谢物的速率高20倍（CL(int)：内酯为923±965，而酸为45.8±59.1微升·分钟⁻¹·毫克⁻¹）。阿托伐他汀内酯抑制人肝微粒体对阿托伐他汀酸的代谢，抑制常数（K(i)）为0.9微摩尔，而阿托伐他汀内酯对阿托伐他汀的K(i)为90微摩尔。与CYP3A4复合的阿托伐他汀酸和阿托伐他汀内酯的结合自由能计算表明，与阴离子酸相比，中性内酯较小的去溶剂化能是内酯具有更高结合亲和力的主要原因，而非熵优势。由于阿托伐他汀内酯具有显著更高的代谢清除率，且内酯是阿托伐他汀酸代谢的强抑制剂，可以预期内酯的代谢是阿托伐他汀消除和药物相互作用的相关途径。我们推测，人血浆中存在的大多数开放酸代谢物是由内酯代谢物的相互转化产生的。
