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Influence of CYP3A enzymes and ABC transporters on the activity of tyrosine kinase inhibitors in chronic myeloid leukemia
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1370
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-97427ISBN: 978-91-7519-576-6 (print)OAI: oai:DiVA.org:liu-97427DiVA: diva2:647746
Public defence
2013-10-25, Nils-Holgersalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2013-09-12Bibliographically approved
List of papers
1. ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro
Open this publication in new window or tab >>ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro
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2013 (English)In: Pharmacogenomics and Personalized Medicine, ISSN 1178-7066, Vol. 6, 63-72 p.Article in journal (Refereed) Published
Abstract [en]

Single-nucleotide polymorphisms (SNPs) in the gene coding for the efflux-transport protein ABCB1 (P-glycoprotein) are commonly inherited as haplotypes. ABCB1 SNPs and haplotypes have been suggested to influence the pharmacokinetics and therapeutic outcome of the tyrosine kinase inhibitor (TKI) imatinib, used for treatment of chronic myeloid leukemia (CML). However, no consensus has yet been reached with respect to the significance of variant ABCB1 in CML treatment. Functional studies of variant ABCB1 transport of imatinib as well as other TKIs might aid the interpretation of results from in vivo association studies, but are currently lacking. The aim of this study was to investigate the consequences of ABCB1 variant haplotypes for transport and efficacy of TKIs (imatinib, its major metabolite N-desmethyl imatinib [CGP74588], dasatinib, nilotinib, and bosutinib) in CML cells. Variant haplotypes - including the 61A>G, 1199G>A, 1236C>T, 1795G>A, 2677G>T/A, and 3435T>C SNPs - were constructed in ABCB1 complementary DNA and transduced to K562 cells using retroviral gene transfer. The ability of variant cells to express ABCB1 protein and protect against TKI cytotoxicity was investigated. It was found that dasatinib and the imatinib metabolite CGP74588 are effectively transported by ABCB1, while imatinib, nilotinib, and bosutinib are comparatively weaker ABCB1 substrates. None of the investigated haplotypes altered the protective effect of ABCB1 expression against TKI cytotoxicity. These findings imply that the ABCB1 haplotypes investigated here are not likely to influence TKI pharmacokinetics or therapeutic efficacy in vivo.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97421 (URN)10.2147/PGPM.S45522 (DOI)24019750 (PubMedID)
Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2017-12-06Bibliographically approved
2. Influence of variant ABCG2 on tyrosine kinase inhibitor transport and efficacy in the K562 chronic myeloid leukemia cell line
Open this publication in new window or tab >>Influence of variant ABCG2 on tyrosine kinase inhibitor transport and efficacy in the K562 chronic myeloid leukemia cell line
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ABCG2. Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs (imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib and bosutinib). Methods: ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G and 1582G>A were constructed from ABCG2 wild type cDNA and transduced to K562 cells by retroviral gene transfer. The ability of variant cells to express ABCG2 in the cell membrane and protect against TKI cytotoxicity was investigated. Results: Wild type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided a better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib and nilotinib cytotoxicity. The most prominent effect was found for the 623T>C SNP which resulted in undetectable ABCG2 expression and low protection against TKI cytotoxicity. Conclusion: These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C and 1574T>G impair ABCG2 transport function and might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is to a greater extent than the parent compound transported by ABCG2.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97423 (URN)
Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2014-04-22Bibliographically approved
3. CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity
Open this publication in new window or tab >>CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity
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2010 (English)In: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, ISSN 0031-6970, Vol. 66, no 4, 383-386 p.Article in journal (Refereed) Published
Abstract [en]

Imatinib is currently used for the treatment of chronic myeloid leukemia (CML). The main metabolite CGP74588 has similar potency to that of imatinib and is a product of CYP3A4 and CYP3A5 metabolism. However, the clinical significance of the metabolism on therapeutic response and pharmacokinetics is still unclear. We designed this study to investigate the role of the CYP3A activity in the response to imatinib therapy. Fourteen CML patients were phenotyped for in vivo CYP3A activity using quinine as a probe drug. The plasma concentration ratio of quinine and its CYP3A metabolite was used for assessing CYP3A activity. The patients were divided into complete molecular responders with undetectable levels of BCR-ABL transcripts after 12 months of therapy and into partial molecular responders who had failed to achieve a complete molecular response. Patients that achieved complete molecular response showed significantly (Mann-Whitney U-test, p = 0.013) higher in vivo CYP3A activity (median quinine metabolic ratio = 10.1) than patients achieving partial molecular response (median = 15.9). These results indicate a clinical significance of the CYP3A activity and its metabolic products in CML patients treated with imatinib.

Keyword
Chronic myeloid leukemia, Imatinib, CYP3A4, CYP3A5, CGP74588, Complete molecular response
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54710 (URN)10.1007/s00228-009-0772-y (DOI)000275710200008 ()
Note

The original publication is available at www.springerlink.com: Henrik Green, Karin Skoglund, Franz Rommel, Rajaa A Mirghani and Kourosh Lotfi, CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity, 2010, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, (66), 4, 383-386. http://dx.doi.org/10.1007/s00228-009-0772-y Copyright: Springer Science Business Media http://www.springerlink.com/

Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2014-01-09Bibliographically approved
4. In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
Open this publication in new window or tab >>In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
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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
Identifiers
urn:nbn:se:liu:diva-97425 (URN)
Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2013-09-12Bibliographically approved

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