Privacy in clinical information systems in secondary careCommentary: Let's discuss wider social and professional issuesCommentary: Organisational and cultural aspects are also important

Abstract

Lapatinib, an oral breast cancer drug, has recently been reported to be a mechanism-based inactivator of cytochrome P450 (P450) 3A4 and also an idiosyncratic hepatotoxicant. It also was suggested that formation of a reactive quinoneimine metabolite was possibly involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. LC-MS analysis of P450 3A4 after incubation with lapatinib did not exhibit any peak corresponding to irreversible modifications. The enzymatic activity inactivated by lapatinib was completely restored by the addition of potassium ferricyanide. These results indicate that the mechanism of MBI by lapatinib is quasi-irreversible and mediated via metabolic-intermediate (MI) complex formation. This was verified by the increase of a signature Soret absorbance at around 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: <i>N</i>-hydroxy lapatinib (M3) and the oxime form of <i>N</i>-dealkylated lapatinib (M2), suggesting that a nitroso or another related intermediate generated from M3 is involved in MI complex formation. In contrast, P450 3A5 was much less susceptible to MBI by lapatinib via MI complex formation than P450 3A4. Also, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with <i>N</i>-hydroxylation as the initial step in the pathway to MI complex formation. In conclusion, our results demonstrate that the primary mechanism for MBI of P450 3A4 by lapatinib is not irreversible modification by the quinoneimine metabolite, but quasi-irreversible MI complex formation mediated via oxidation of the secondary amine group of lapatinib.