Prakash Chandra, Johnson Kim A, Schroeder Clinton M, Potchoiba Michael J
Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA.
Drug Metab Dispos. 2008 Sep;36(9):1753-69. doi: 10.1124/dmd.108.021808. Epub 2008 May 30.
Disposition of lasofoxifene (LAS; 6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol. tartrate) was investigated in rats and monkeys after oral administration of a single oral dose of [(14)C]LAS. Total mean recoveries of the radiocarbon were 96.7 and 94.3% from rats and monkeys, respectively. The major route of excretion in both species was the feces, and based on a separate study in the bile duct-cannulated rat, this likely reflects excretion in bile rather than incomplete absorption. Whole-body autoradioluminography suggested that [(14)C]LAS radioequivalents distributed rapidly in the rat with most tissues achieving maximal concentrations at 1 h. Half-life of radioactivity was longest in the uvea (124 h) and shortest in the spleen ( approximately 3 h). LAS was extensively metabolized in both rats and monkeys because no unchanged drug was detected in urine and/or bile. Based on area under the curve((0-24)) values, >78% of the circulating radioactivity was due to the metabolites. A total of 22 metabolites were tentatively identified by liquid chromatography-tandem mass spectrometry. Based on the structures of the metabolites, six metabolic pathways of LAS were identified: hydroxylation at the tetraline ring, hydroxylation at the aromatic ring attached to tetraline, methylation of the catechol intermediates by catechol-O-methyl transferase, oxidation at the pyrrolidine ring, and direct conjugation with glucuronic acid and sulfuric acid. LAS and its glucuronide conjugate (M7) were the major circulating drug-related moieties in both rats and monkeys. However, there were notable species-related qualitative and quantitative differences in the metabolic profiles. The catechol (M21) and its sulfate conjugate (M10) were observed only in monkeys, whereas the glucuronide conjugate of the methylated catechol (M8) and hydroxy-LAS (M9) were detected only in rats.
在大鼠和猴子口服单剂量[(14)C]拉索昔芬（LAS；6-苯基-5-[4-(2-吡咯烷-1-基-乙氧基)-苯基]-5,6,7,8-四氢萘-2-醇酒石酸盐）后，对其处置情况进行了研究。大鼠和猴子体内放射性碳的总平均回收率分别为96.7%和94.3%。两种动物的主要排泄途径均为粪便，根据一项对胆管插管大鼠的单独研究，这可能反映的是经胆汁排泄而非吸收不完全。全身放射自显影显示[(14)C]LAS放射性等效物在大鼠体内迅速分布，大多数组织在1小时时达到最大浓度。放射性半衰期在葡萄膜中最长（124小时），在脾脏中最短（约3小时）。LAS在大鼠和猴子体内均被广泛代谢,因为在尿液和/或胆汁中未检测到未变化的药物。根据曲线下面积((0 - 24))值，超过78%的循环放射性是由代谢物引起的。通过液相色谱 - 串联质谱法初步鉴定出总共22种代谢物。根据代谢物的结构，确定了LAS的六种代谢途径：四氢萘环羟基化、与四氢萘相连的芳环羟基化、儿茶酚中间产物经儿茶酚 - O - 甲基转移酶甲基化、吡咯烷环氧化以及与葡萄糖醛酸和硫酸直接结合。LAS及其葡萄糖醛酸结合物（M7）是大鼠和猴子体内主要的循环药物相关部分。然而，在代谢谱方面存在显著的种属相关定性和定量差异。儿茶酚（M21）及其硫酸盐结合物（M10）仅在猴子中观察到，而甲基化儿茶酚的葡萄糖醛酸结合物（M8）和羟基 - LAS（M9）仅在大鼠中检测到。
