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1.
Drug Metab Dispos ; 39(6): 1022-30, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21363997

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 was suggested that formation of a reactive quinoneimine metabolite was involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. Liquid chromatography-mass spectrometry analysis of P450 3A4 after incubation with lapatinib did not show 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 complex (MI complex) formation. This finding was verified by the increase in a signature Soret absorbance at approximately 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: N-hydroxy lapatinib (M3) and the oxime form of N-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. In addition, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with N-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.


Subject(s)
Antineoplastic Agents/metabolism , Cytochrome P-450 CYP3A Inhibitors , Quinazolines/metabolism , Antineoplastic Agents/toxicity , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/etiology , Chromatography, Liquid , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Enzyme Activation , Escherichia coli/genetics , Ferricyanides/pharmacology , Humans , Lapatinib , Mass Spectrometry , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Molecular Structure , Oxidation-Reduction , Protein Binding , Quinazolines/toxicity
2.
Drug Metab Dispos ; 38(6): 963-72, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20200233

ABSTRACT

Three secondary amines desipramine (DES), (S)-fluoxetine [(S)-FLX], and N-desmethyldiltiazem (MA) undergo N-hydroxylation to the corresponding secondary hydroxylamines [N-hydroxydesipramine, (S)-N-hydroxyfluoxetine, and N-hydroxy-N-desmethyldiltiazem] by cytochromes P450 2C11, 2C19, and 3A4, respectively. The expected primary amine products, N-desmethyldesipramine, (S)-norfluoxetine, and N,N-didesmethyldiltiazem, are also observed. The formation of metabolic-intermediate (MI) complexes from these substrates and metabolites was examined. In each example, the initial rates of MI complex accumulation followed the order secondary hydroxylamine > secondary amine >> primary amine, suggesting that the primary amine metabolites do not contribute to formation of MI complexes from these secondary amines. Furthermore, the primary amine metabolites, which accumulate in incubations of the secondary amines, inhibit MI complex formation. Mass balance studies provided estimates of the product ratios of N-dealkylation to N-hydroxylation. The ratios were 2.9 (DES-CYP2C11), 3.6 [(S)-FLX-CYP2C19], and 0.8 (MA-CYP3A4), indicating that secondary hydroxylamines are significant metabolites of the P450-mediated metabolism of secondary alkyl amines. Parallel studies with N-methyl-d(3)-desipramine and CYP2C11 demonstrated significant isotopically sensitive switching from N-demethylation to N-hydroxylation. These findings demonstrate that the major pathway to MI complex formation from these secondary amines arises from N-hydroxylation rather than N-dealkylation and that the primary amines are significant competitive inhibitors of MI complex formation.


Subject(s)
Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP3A/metabolism , Desipramine/analogs & derivatives , Diltiazem/analogs & derivatives , Fluoxetine/pharmacology , Imipramine/analogs & derivatives , Microsomes, Liver/metabolism , Cytochrome P-450 CYP2B6 , Cytochrome P-450 CYP2C19 , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 2 , Desipramine/metabolism , Desipramine/pharmacology , Diltiazem/metabolism , Fluoxetine/analogs & derivatives , Fluoxetine/metabolism , Humans , Hydroxylamine , Hydroxylamines/metabolism , Hydroxylation , Imipramine/metabolism , Imipramine/pharmacology , Oxidoreductases, N-Demethylating/metabolism , Steroid 16-alpha-Hydroxylase/metabolism
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