IDENTIFICATION OF THE HUMAN P450 ENZYMES INVOLVED IN LANSOPRAZOLE METABOLISM

The aim of this study was to identify which human P450 enzymes are inv olved 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 lanso prazole sulfone appeared to be catalyzed by a single, low-affinity enz yme (apparent K-m similar to 100 mu M). In contrast, lansoprazole 5-hy droxylation appeared to be catalyzed by two kinetically distinct enzym es (apparent K-m similar to 100 mu M and similar to 15 mu M). When hum an liver microsomes (n = 16) were incubated with 100 mu M lansoprazole , both the 5-hydroxylation and sulfoxidation of lansoprazole appeared to be catalyzed by CYP3A4/5 (based on correlation analyses). Antibodie s against rat CYP3A enzymes inhibited the rate of both 5-hydroxylation (similar to 55%) and sulfoxidation (similar to 70%) and cDNA-expresse d CYP3A4 catalyzed both the 5-hydroxylation and sulfoxidation of lanso prazole (apparent K-m similar to 100 mu M). However, at the pharmacolo gically relevant substrate concentration of 1 mu M, lansoprazole sulfo xidation was still highly correlated with CYP3A4/5 activity (r(2) = .9 05), but lansoprazole 5-hydroxylation appeared to be catalyzed by CYP2 C19 (r(2) = .875) rather than CYP3A4/5 (r(2) = .113). Antibodies and c hemical inhibitors of CYP2C enzymes preferentially inhibited the 5-hyd roxylation of lansoprazole, whereas lansoprazole sulfoxidation was pre ferentially inhibited by antibodies and chemical inhibitors of CYP3A4/ 5. The cDNA expressed enzymes CYP2C8, CYP2C9 and CYP2C19 catalyzed var ying rates of lansoprazole 5-hydroxylation at a substrate concentratio n of 50 mu M, but only CYPC19 catalyzed this reaction at 1 mu M. These results suggest that, at pharmacologically relevant concentrations, t he 5-hydroxylation of lansoprazole is primarily catalyzed by CYP2C19, whereas the sulfoxidation of lansoprazole is primarily catalyzed by CY P3A4/5. It is possible that individuals lacking CYP2C19 will be poor m etabolizers of lansoprazole.