Identification of the human P450 enzymes involved in lansoprazole metabolism

Abstract

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.