Participation of CYP2C8 and CYP3A4 in the N‐demethylation of imatinib in human hepatic microsomes

Nebot, Noelia; Crettol, Séverine; D'Esposito, Fabrizio; Tattam, Bruce N.; Hibbs, David E.; Murray, Michael T.

doi:10.1111/j.1476-5381.2010.00946.x

Cited by 75 publications

(73 citation statements)

References 37 publications

(55 reference statements)

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“…However, we cannot exclude an additional influence of imatinib. As a potent CYP3A4 inhibitor, imatinib could theoretically increase the exposure to vincristine and dexamethasone, both of which are metabolized by the enzyme (Duckett & Cameron, 2010;Green et al, 2010;Nebot et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Treatment of Philadelphia chromosome‐positive acute lymphoblastic leukaemia with imatinib combined with a paediatric‐based protocol

Thyagu¹,

Minden²,

Gupta³

et al. 2012

Br J Haematol

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SummaryAlthough the combination of tyrosine kinase inhibitors with chemotherapy is widely used for young adults with Philadelphia chromosome positiveacute lymphoblastic leukaemia (Ph+ ALL), the outcome and safety of this combination using intensive paediatric-based protocols has not been well described. The clinical course of 32 adults age 18-60 years with Ph+ ALL treated with a paediatric-based protocol plus imatinib was evaluated. The complete response rate was 94%. Grade 3-4 infections, neuropathy, myopathy and liver function abnormalities were common, resulting in major treatment delays and dose reductions, and declines in performance status (physical deconditioning), particularly in patients aged 41-60 years. Median and 3-year overall survival (OS) was 40·7 months and 53%, respectively, and median and 3-year even-free survival (EFS) was 30·1 months and 50%, respectively. OS and EFS were inferior in deconditioned patients. Of 16 patients who underwent haematopoietic stem cell transplantation (HSCT) in first complete remission, six died of non-relapse complications. There was no significant difference in OS and EFS between transplanted and nontransplanted patients, based on an intention-to-treat and time-to-donor identification analysis. The combination of imatinib with a paediatric-based regimen in adults produced high response rates, but was associated with considerable toxicity and high non-relapse mortality post-HSCT.Keywords: leukaemia, chemotherapy, haematopoietic stem cell transplantation, acute lymphoblastic leukaemia, tyrosine kinase inhibitors.Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) has long been recognized as a high-risk subset of ALL. Published data show a disappointing longterm survival of 20% or less with chemotherapy alone (Dombret et al, 2002;Faderl et al, 2010). The combination of BCR-ABL1 targeted tyrosine kinase inhibitors (TKIs), most commonly imatinib, with multi-agent chemotherapy regimens has improved outcomes, with complete response rates of 80-90%, and 5-year survivals in the 35-50% range (Thomas et al, 2004;Yanada et al, 2006; de Labarthe et al, 2007;Bassan et al, 2010;Fielding, 2010). Nevertheless, Ph+ disease remains a poor prognosis subgroup with unacceptably high relapse rates.Allogeneic haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) remains the standard of care in most centres, and is the only treatment demonstrated to cure a significant proportion of patients. Consequently, the goal of most approaches is to optimize complete response rates and prolong remission duration, thereby permitting a larger proportion of patients to proceed to HSCT in CR1. The outcome of HSCT is largely influenced by transplant-related mortality (TRM) and post-transplant relapse. Early TRM is influenced by various factors, including pretransplant patient-related issues, toxicity of the conditioning regimen, and graft-versus-host disease (GVHD) (Sorror et al, 2005;Artz et al, 2006).For Ph-negative ALL, a number of studies in adolescents ...

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Section: Discussionmentioning

confidence: 99%

Treatment of Philadelphia chromosome‐positive acute lymphoblastic leukaemia with imatinib combined with a paediatric‐based protocol

Thyagu¹,

Minden²,

Gupta³

et al. 2012

Br J Haematol

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“…C.5; Suttle et al, 2015). Imatinib, the first tyrosine kinase inhibitor approved for clinical use, is metabolized by several CYP enzymes in vitro, with CYP2C8 and CYP3A4 being the most important ones (Nebot et al, 2010;Filppula et al, 2013a). CYP3A4 is involved in several metabolic pathways of imatinib, whereas CYP2C8 only catalyzes the formation of the main metabolite, N-demethylimatinib (Table 4; Rochat et al, 2008;Filppula et al, 2013a).…”

Section: A Drugsmentioning

confidence: 99%

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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“…eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/ 000406/WC500022207.pdf, http://www.accessdata.fda.gov/drugsatfda_ docs/nda/2001/21335_Gleevec.cfm) (Rochat et al, 2008;Nebot et al, 2010). Recently, however, we demonstrated that imatinib is a potent mechanism-based inhibitor of this enzyme in vitro, and clinically relevant imatinib concentrations were predicted to cause up to 90% inhibition of hepatic CYP3A4 activity (Filppula et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Autoinhibition of CYP3A4 Leads to Important Role of CYP2C8 in Imatinib Metabolism: Variability in CYP2C8 Activity May Alter Plasma Concentrations and Response

Filppula¹,

Neuvonen²,

Laitila³

et al. 2012

Drug Metab Dispos

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Recent data suggest that the role of CYP3A4 in imatinib metabolism is smaller than presumed. This study aimed to evaluate the quantitative importance of different cytochrome P450 (P450) enzymes in imatinib pharmacokinetics. First, the metabolism of imatinib was investigated using recombinant P450 enzymes and human liver microsomes with P450 isoform-selective inhibitors. Thereafter, an in silico model for imatinib was constructed to perform pharmacokinetic simulations to assess the roles of P450 enzymes in imatinib elimination at clinically used imatinib doses. In vitro, CYP2C8 inhibitors and CYP3A4 inhibitors inhibited the depletion of 0.1 mM imatinib by 45 and 80%, respectively, and the formation of the main metabolite of imatinib, N-desmethylimatinib, by >50%. Likewise, recombinant CYP2C8 and CYP3A4 metabolized imatinib extensively, whereas other isoforms had minor effect on imatinib concentrations.In the beginning of imatinib treatment, the fractions of its hepatic clearance mediated by CYP2C8 and CYP3A4 were predicted to approximate 40 and 60%, respectively. During long-term treatment with imatinib 400 mg once or twice daily, up to 65 or 75% of its hepatic elimination was predicted to occur via CYP2C8, and only about 35 or 25% by CYP3A4, due to dose-and timedependent autoinactivation of CYP3A4 by imatinib. Thus, although CYP2C8 and CYP3A4 are the main enzymes in imatinib metabolism in vitro, in silico predictions indicate that imatinib inhibits its own CYP3A4-mediated metabolism, assigning a key role for CYP2C8. During multiple dosing, pharmacogenetic polymorphisms and drug interactions affecting CYP2C8 activity may cause marked interindividual variation in the exposure and response to imatinib.

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Participation of CYP2C8 and CYP3A4 in the N‐demethylation of imatinib in human hepatic microsomes

Cited by 75 publications

References 37 publications

Treatment of Philadelphia chromosome‐positive acute lymphoblastic leukaemia with imatinib combined with a paediatric‐based protocol

Treatment of Philadelphia chromosome‐positive acute lymphoblastic leukaemia with imatinib combined with a paediatric‐based protocol

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Autoinhibition of CYP3A4 Leads to Important Role of CYP2C8 in Imatinib Metabolism: Variability in CYP2C8 Activity May Alter Plasma Concentrations and Response

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