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In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
Department of Hematology and Coagulation, Skåne University Hospital, Lund, Sweden.
Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: The hepatic enzymes CYP3A4 and CYP3A5 metabolize the tyrosine kinase inhibitor imatinib into a large number of metabolites including the pharmacologically active N-desmethyl imatinib (CGP74588). Because the metabolic activity of CYP3A varies considerably between individuals and a previous pilot study suggested an inverse association between in vivo CYP3A metabolic activity and therapeutic outcome of imatinib, the primary aim of this study was to investigate the influence of CYP3A metabolic activity on the outcome of imatinib therapy in chronic myeloid leukemia patients.

Methods: Fifty-five patients were included and CYP3A activity was estimated in vivo using quinine as a probe drug. Imatinib and CGP74588 trough concentrations in the plasma were determined at steady state in 34 patients. Cytogenetic and molecular responses after 12 months of first-line imatinib were retrospectively collected from patients’ medical records.

Results: Patients with optimal response to imatinib (complete cytogenetic response (CCgR) or molecular response of BCR-ABL <1%) did not have different levels of CYP3A activity compared to non-optimal responders. Similar results were found when analyzing the molecular response and CCgR separately. Neither the imatinib trough concentration nor the CGP74588/imatinib ratio were significantly associated with CYP3A activity.

Conclusion: CYP3A enzyme activity, as measured by quinine metabolic ratio, does not correlate with the plasma concentrations of imatinib or CGP74588 and is not predictive of imatinib therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the   ratelimiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes such as plasma protein binding or transport protein activity to look for the major contributor to patient variability in imatinib plasma concentration.

National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-97425OAI: diva2:647719
Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2013-09-12Bibliographically approved
In thesis
1. Influence of CYP3A enzymes and ABC transporters on the activity of tyrosine kinase inhibitors in chronic myeloid leukemia
Open this publication in new window or tab >>Influence of CYP3A enzymes and ABC transporters on the activity of tyrosine kinase inhibitors in chronic myeloid leukemia
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The introduction of imatinib, a tyrosine kinase inhibitor (TKI), in the treatment of chronic myeloid leukemia (CML) was a major break-through and the first drug that was successfully designed to target the specific mechanism of a malignant disease. Imatinib still remains as the standard treatment of newly diagnosed CML patients although a second generation of TKIs has also been approved for first-line CML treatment.

Most patients achieve a good therapeutic effect with imatinib, but some patients are resistant to the drug and are at greater risk of disease progression. In order to further improve CML treatment, a better understanding of the underlying reasons for variable responses to imatinib and the second generation TKIs is important.

A number of potential determinants of imatinib response have been suggested, including interindividual variability in pharmacokinetics. Variations in drug metabolism and cellular transport might contribute to the large variations observed in imatinib plasma concentrations and might, therefore, affect the amount of drug that reaches target CML cells. Imatinib is primarily metabolized by the CYP3A hepatic enzymes that are known to be highly variable in activity between different individuals. Imatinib is also a substrate of the ABCB1 and ABCG2 efflux pumps that potentially regulate the elimination of imatinib from the plasma. The ABCB1 and ABCG2 genes are polymorphic and contain single nucleotide polymorphisms (SNPs) that might influence the transport capacity of these proteins. The primary aim of the present thesis was to investigate the influence of CYP3A metabolic activity and cellular transport mediated by genetic variants of ABCB1 and ABCG2 on the response to imatinib and the second generation TKIs used for CML therapy.

In vivo CYP3A activity and plasma concentrations of imatinib and its pharmacologically active metabolite CGP74588 were analyzed in CML patients treated with imatinib. CYP3A phenotypes were correlated to plasma concentrations and imatinib outcome 12 months after initiation of treatment. The influence of ABC transport on TKI efficacy was evaluated in vitro by the transduction of genetic variants of ABCB1 and ABCG2 into the CML cell line K562. Functionality of the transport proteins was evaluated by measuring protein expression levels on the cell surface, the intracellular accumulation of TKIs, and the ability of ABCB1 and ABCG2 variants to protect cells from TKI cytotoxicity.

We found that CYP3A metabolic activity does not influence the drug plasma concentrations or the therapeutic outcome of imatinib in CML patients. These findings indicate that even though imatinib is primarily metabolized by CYP3A this metabolic activity is not the rate-limiting step in imatinib elimination. CYP3A activity, therefore, is not a suitable predictive marker of imatinib outcome. The in vitro studies revealed that the ABCB1 variants investigated here do not alter the transport of imatinib, CGP74588, dasatinib, or nilotinib. In contrast, the ABCG2 SNPs 421C>A, 623T>C, 886G>C, and 1574T>G significantly impaired the cellular efflux of imatinib, CGP74588, dasatinib, and nilotinib and could possibly influence transport of these TKIs in vivo. It was also found that CGP74588 is by far a better substrate than imatinib for both ABCB1 and ABCG2, and this might have implications in patients with high levels of CYP3A activity. In conclusion, our studies show that ABCG2 SNPs might be important for prediction of imatinib outcome in vivo. On the other hand, CYP3A activity and the ABCB1 SNPs investigated in this study are not likely to be useful as predictors of imatinib outcome.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 77 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1370
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-97427 (URN)978-91-7519-576-6 (ISBN)
Public defence
2013-10-25, Nils-Holgersalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2013-09-12Bibliographically approved

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Skoglund, KarinVikingsson, SvanteSandstedt, AnnaHägg, StaffanPeterson, CurtLotfi, KouroshGreen, Henrik
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