Revisiting the Metabolism of Ketoconazole Using Accurate Mass

Abstract

The microsomal metabolism of ketoconazole is revisited using accurate mass LC/MS(n) and deuterium labelling. Structures for sixteen metabolites are proposed from rat and human microsomal metabolism of commercial ketoconazole. Thirteen of the proposed structures are well determined and consistent with all data; five of the proposed structures are less certain. Ten of the metabolites are described for the first time. Reaction phenotyping shows that most of the metabolites arise from CYP3A4, the enzyme known to be well inhibited by ketoconazole.

The Effects on Metabolic Clearance when Administering a Potent CYP3A Autoinducer with the Prototypic CYP3A Inhibitor, Ketoconazole

“…The mechanism of ketoconazole clearance is poorly documented in the literature; however, there is evidence to suggest that it may be at least partly metabolized by CYP3A (Doble et al, 1988;Fitch et al, 2009). Although the results of this study appear to support that CYP3A is a significant clearance pathway for ketoconazole, it cannot be discounted that semagacestat may also induce other P450 enzymes or transporters via PXR or constitutive active/androstane receptor pathways, which may account for potential alternative clearance mechanisms for ketoconazole.…”

“…Two reports in the literature have suggested that CYP3A plays some role in ketoconazole elimination (Doble et al, 1988;Fitch et al, 2009). Nevertheless, our search of the literature revealed no clinical trial data showing the effect of a CYP3A inducer or inhibitor on the pharmacokinetics of ketoconazole.…”

Defining Human Pathways of Drug Metabolism In Vivo through the Development of a Multiple Humanized Mouse Model

“…The human to mouse dose translation described above does not account for the rate of drug elimination (Reagan-Shaw et al, 2008). Considering the strong induction of CYP3A4 activity in the RIF-treated hPXR/CAR/CYP3A4/7/2D6/2C9 mice and the relatively rapid elimination of the CYP3A4 substrate KTZ (Fitch et al, 2009) from the systemic circulation, the dose of the inhibitor in the induced hPXR/CAR/CYP3A4/7/2D6/2C9 mice has to be adjusted for the high activity of the major eliminating enzyme to adequately reflect the interaction of KTZ and MDZ in humans. An empirical method of the irinotecan dose calculation was developed to account for the interindividual variations of activities of CYP3A4 in humans, which required the collection of extensive in vivo experimental data (van der Bol et al, 2010).…”

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

“…In the 1980s, trace quantities of glucuronic acid and sulfate conjugates were reported in rat excreta [6]. Remarkable progress in the understanding of KCZ metabolism was made beginning in the 1990s [7,8,9,10,11,12]. Whitehouse et al [7,8] identified nine metabolites of KCZ in mouse liver and reported that N -deacetylation was the primary metabolic pathway.…”