Pearce R E, Rodrigues A D, Goldstein J A, Parkinson A
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, USA.
J Pharmacol Exp Ther. 1996 May;277(2):805-16.
The aim of this study was to identify which human P450 enzymes are involved in the metabolism of lansoprazole. In the presence of NADPH and oxygen, human liver microsomes converted lansoprazole to lansoprazole sulfide, lansoprazole sulfone and 5-hydroxylansoprazole. Formation of lansoprazole sulfide occurred nonenzymatically. The formation of lansoprazole sulfone appeared to be catalyzed by a single, low-affinity enzyme (apparent Km approximately 100 microM). In contrast, lansoprazole 5-hydroxylation appeared to be catalyzed by two kinetically distinct enzymes (apparent Km approximately 100 microM and approximately 15 microM). When human liver microsomes (n = 16) were incubated with 100 microM lansoprazole, both the 5-hydroxylation and sulfoxidation of lansoprazole appeared to be catalyzed by CYP3A4/5 (based on correlation analyses). Antibodies against rat CYP3A enzymes inhibited the rate of both 5-hydroxylation (approximately 55%) and sulfoxidation (approximately 70%) and cDNA-expressed CYP3A4 catalyzed both the 5-hydroxylation and sulfoxidation of lansoprazole (apparent Km approximately 100 microM). However, at the pharmacologically relevant substrate concentration of 1 microM, lansoprazole sulfoxidation was still highly correlated with CYP3A4/5 activity (r2 = .905), but lansoprazole 5-hydroxylation appeared to be catalyzed by CYP2C19 (r2 = .875) rather than CYP3A4/5 (r2 = .113). Antibodies and chemical inhibitors of CYP2C enzymes preferentially inhibited the 5-hydroxylation of lansoprazole, whereas lansoprazole sulfoxidation was preferentially inhibited by antibodies and chemical inhibitors of CYP3A4/5. The cDNA expressed enzymes CYP2C8, CYP2C9 and CYP2C19 catalyzed varying rates of lansoprazole 5-hydroxylation at a substrate concentration of 50 microM, but only CYPC19 catalyzed this reaction at 1 microM. These results suggest that at pharmacologically relevant concentrations, the 5-hydroxylation of lansoprazole is primarily catalyzed by CYP2C19, whereas the sulfoxidation of lansoprazole is primarily catalyzed by CYP3A4/5. It is possible that individuals lacking CYP2C19 will be poor metabolizers of lansoprazole.
本研究的目的是确定哪些人细胞色素P450酶参与兰索拉唑的代谢。在存在NADPH和氧气的情况下，人肝微粒体将兰索拉唑转化为兰索拉唑硫化物、兰索拉唑砜和5-羟基兰索拉唑。兰索拉唑硫化物的形成是非酶促反应。兰索拉唑砜的形成似乎由一种单一的、低亲和力的酶催化（表观Km约为100 microM）。相比之下，兰索拉唑的5-羟基化似乎由两种动力学特性不同的酶催化（表观Km约为100 microM和约15 microM）。当用人肝微粒体（n = 16）与100 microM兰索拉唑孵育时，兰索拉唑的5-羟基化和硫氧化似乎均由CYP3A4/5催化（基于相关性分析）。抗大鼠CYP3A酶的抗体抑制了5-羟基化（约55%）和硫氧化（约70%）的速率，并且cDNA表达的CYP3A4催化了兰索拉唑的5-羟基化和硫氧化（表观Km约为100 microM）。然而，在药理学相关的1 microM底物浓度下，兰索拉唑硫氧化仍与CYP3A4/5活性高度相关（r2 = 0.905），但兰索拉唑的5-羟基化似乎由CYP2C19催化（r2 = 0.875）而非CYP3A4/5（r2 = 0.113）。CYP2C酶的抗体和化学抑制剂优先抑制兰索拉唑的5-羟基化，而兰索拉唑硫氧化优先被CYP3A4/5的抗体和化学抑制剂抑制。cDNA表达的酶CYP2C8、CYP2C9和CYP2C19在50 microM底物浓度下催化兰索拉唑5-羟基化的速率不同，但只有CYPC19在1 microM时催化此反应。这些结果表明，在药理学相关浓度下，兰索拉唑的5-羟基化主要由CYP2C19催化，而兰索拉唑的硫氧化主要由CYP3A4/5催化。缺乏CYP2C19的个体可能是兰索拉唑的代谢不良者。
