Identification and characterization of efavirenz metabolites by liquid chromatography/mass spectrometry and high field NMR: species differences in the metabolism of efavirenz.
Identification and characterization of efavirenz metabolites by liquid chromatography/mass spectrometry and high field NMR: species differences in the metabolism of efavirenz.
复制标题
通过液相色谱/质谱和高场核磁共振对依非韦伦代谢物进行鉴定和表征：依非韦伦代谢的物种差异。
DOI：
--
复制
发表时间：
1999
影响因子：
3.9
通讯作者：
D. Christ
中科院分区：
文献类型：
--
作者：
A. Mutlib;H. Chen;G. Németh;J. Markwalder;S. Seitz;L. Gan;D. Christ
Efavirenz（Sustiva，图 1）是一种有效且特异性的 HIV-1 逆转录酶抑制剂，已被批准用于治疗 HIV 感染。为了检查物种间代谢的潜在差异，获得并比较了大鼠、豚鼠、仓鼠、食蟹猴和人类尿液中依非韦伦代谢物的液相色谱/质谱图谱。分离了依非韦伦的代谢物，并通过质谱和核磁共振分析明确确定了结构。依非韦伦在所有物种中被广泛代谢，尿液中没有或痕量母体化合物的排泄就证明了这一点。观察到依非韦伦代谢存在显着的物种差异。所有物种尿液中排泄的主要代谢物是8-羟基化代谢物的O-葡萄糖醛酸结合物(M1)。依非韦伦还通过与葡萄糖醛酸直接结合而被代谢，在所有五个物种中形成 N-葡萄糖醛酸苷 (M2)。在大鼠和食蟹猴的尿液中发现了 8-OH 依非韦伦 (M3) 的硫酸盐结合物，但在人类中未发现。除了芳环羟基化产物外，还分离出具有羟基化环丙烷环（C14）的代谢物。在大鼠和豚鼠体内发现了依非韦伦的 GSH 相关产物。由 GSH 加合物 (M9) 形成的半胱氨酰甘氨酸加合物 (M10) 仅在大鼠和豚鼠尿液中发现大量，在其他物种中未检测到。体外代谢研究表明，GSH 加合物是在仅存在大鼠肝脏和肾脏亚细胞组分的情况下由环丙醇中间体 (M11) 产生的，而不是由人类或食蟹猴的类似制剂形成的。这些研究表明，大鼠体内存在一种特定的谷胱甘肽-S-转移酶，能够将环丙醇代谢物 (M11) 代谢为 GSH 加合物 M9。根据一些体外结果，提出了依非韦伦在不同物种中的生物转化途径。
Efavirenz (Sustiva, Fig. 1) is a potent and specific inhibitor of HIV-1 reverse transcriptase approved for the treatment of HIV infection. To examine the potential differences in the metabolism among species, liquid chromatography/mass spectrometry profiles of efavirenz metabolites in urine of rats, guinea pigs, hamsters, cynomolgus monkeys, and humans were obtained and compared. The metabolites of efavirenz were isolated, and structures were determined unequivocally by mass spectral and NMR analyses. Efavirenz was metabolized extensively by all the species as evidenced by the excretion of none or trace quantities of parent compound in urine. Significant species differences in the metabolism of efavirenz were observed. The major metabolite excreted in the urine of all species was the O-glucuronide conjugate (M1) of the 8-hydroxylated metabolite. Efavirenz was also metabolized by direct conjugation with glucuronic acid, forming the N-glucuronide (M2) in all five species. The sulfate conjugate of 8-OH efavirenz (M3) was found in the urine of rats and cynomolgus monkeys but not in humans. In addition to the aromatic ring-hydroxylated products, metabolites with a hydroxylated cyclopropane ring (at C14) were also isolated. GSH-related products of efavirenz were identified in rats and guinea pigs. The cysteinylglycine adduct (M10), formed from the GSH adduct (M9), was found in significant quantities in only rat and guinea pig urine and was not detected in other species. In vitro metabolism studies were conducted to show that the GSH adduct was produced from the cyclopropanol intermediate (M11) in the presence of only rat liver and kidney subcellular fractions and was not formed by similar preparations from humans or cynomolgus monkeys. These studies indicated the existence of a specific glutathione-S-transferase in rats capable of metabolizing the cyclopropanol metabolite (M11) to the GSH adduct, M9. The biotransformation pathways of efavirenz in different species were proposed based on some of the in vitro results.
登录
查看更多内容
影响因子：
5.8
作者：
HINCHMAN, CA;BALLATORI, N
通讯作者：
BALLATORI, N
影响因子：
2.9
作者：
Daniel C. Liebler;D. G. Latwesen;Thaddeus C. Reeder
通讯作者：
Daniel C. Liebler;D. G. Latwesen;Thaddeus C. Reeder
细胞毒性和肾毒性 S-缀合物 S-(2-氯-1,1,2-三氟乙基)-L-半胱氨酸的生物激活机制。
DOI：
10.1073/pnas.84.21.7443
发表时间：
1987
影响因子：
11.1
作者：
Dekant,W;Lash,LH;Anders,MW
通讯作者：
Anders,MW
大鼠组织和亚细胞组分中 S-(1,2-二氯乙烯基)谷胱甘肽和 S-(1,2-二氯乙烯基)-L-半胱氨酸（二氯乙炔的谷胱甘肽和半胱氨酸 S-缀合物）的谷胱甘肽依赖性生物合成和生物活化。
DOI：
--
发表时间：
1994
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Patel,N;Birner,G;Dekant,W;Anders,MW
通讯作者：
Anders,MW
去甲洛帕米和去甲维拉帕米的 N-葡萄糖醛酸苷、加洛帕米和维拉帕米的异常代谢物的合成和鉴定。
DOI：
--
发表时间：
1990
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Mutlib,AE;Nelson,WL
通讯作者：
Nelson,WL