Role of CYP2C8 in the metabolism of montelukast and imatinib : Studies in vitro, in silico and in humans
Year: 2014
Type: dissertation
Abstract: The drug-metabolising enzyme cytochrome P450 (CYP) 2C8 is involved in the elimination of several important drugs. The asthma drug montelukast inhibits CYP2C8 potently in vitro, but does not affect the pharmacokinetics of CYP2C8 substrates in vivo. In turn, the cancer drug imatinib is a CYP2C8 and CYP3A4 substrate in vitro, but CYP3A4 inhibitors have little effect on its concentrations in vivo. This thesis aimed to examine these discrepancies, and to study the role of CYP2C8 in the metabolism of montelukast and imatinib. The work comprised in vitro experiments, physiologically based pharmacokinetic (PBPK) simulations, and two interaction studies with a two-phase, placebo-controlled crossover design in healthy subjects. In vitro, CYP2C8 metabolised montelukast extensively. In the clinical study, the strong CYP2C8 inhibitor gemfibrozil increased the area under the plasma concentration time-curve (AUC) of montelukast by 4.5-fold in healthy subjects, thus suggesting that CYP2C8 contributes to ~80% of its elimination. In vitro, imatinib was mainly metabolised by CYP2C8 and CYP3A4, but imatinib also inhibited CYP3A4 irreversibly. In vivo, gemfibrozil unexpectedly reduced imatinib absorption, while it had no effect on imatinib AUC. However, the AUC of the main metabolite of imatinib decreased by ~50%. PBPK simulations suggested that the findings could be explained by a complex interaction involving simultaneous inhibition of an uptake transporter involved in imatinib absorption and of CYP2C8 by gemfibrozil. Furthermore, the simulations proposed that the elimination of imatinib during steady state relies more on CYP2C8 than on CYP3A4, because of CYP3A4 autoinhibition by imatinib. Inhibition of CYP3A4 by imatinib also suggests that concomitant use of imatinib with CYP3A4 substrates may lead to harmful interactions. The findings of this work explain the previously documented in vitro-in vivo inconsistencies and provide important information for a safe use of these drugs. CYP2C8 inhibitors may increase the effect and adverse reactions of montelukast and imatinib. On the other hand, because montelukast is generally well-tolerated and CYP2C8 seems to play a key role in its elimination, these data suggest that it could serve as a CYP2C8 probe in interaction studies. Collectively, the studies of this work strengthen the role of CYP2C8 as an important drug-metabolising enzyme.
Source: Työväentutkimus Vuosikirja
Author: Anne M. Filppula
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1181520158