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Skoglund, Karin
Publications (10 of 21) Show all publications
Gacic, J., Vorkapic, E., Slind Olsen, R., Söderberg, D., Gustafsson, T., Geffers, R., . . . Wågsäter, D. (2016). Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages. Pharmacological Reports, 68(1), 1-6
Open this publication in new window or tab >>Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages
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2016 (English)In: Pharmacological Reports, ISSN 1734-1140, E-ISSN 2299-5684, Vol. 68, no 1, p. 1-6Article in journal (Refereed) Published
Abstract [en]

Background: Imatinib mesylate (Glivec, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). Aim: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. Methods and results: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p < 0.05), acetylated LDL (p < 0.01), and copper-modified oxidized LDL (p < 0.01), respectively. Gel based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. Conclusion: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.

Place, publisher, year, edition, pages
POLISH ACAD SCIENCES INST PHARMACOLOGY, 2016
Keywords
Atherosclerosis; Cholesterol; Imatinib; Macrophages
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-125158 (URN)10.1016/j.pharep.2015.05.024 (DOI)000368567800001 ()26721343 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2013-99X-22231-01-5]

Available from: 2016-02-15 Created: 2016-02-15 Last updated: 2018-07-18
Skoglund, K., Richter, J., Olsson-Stromberg, U., Bergquist, J., Aluthgedara, W., Ubhayasekera, S. J., . . . Green, H. (2016). In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia. Therapeutic Drug Monitoring, 38(2), 230-238
Open this publication in new window or tab >>In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia
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2016 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed) Published
Abstract [en]

Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2016
Keywords
pharmacokinetics; chronic myeloid leukemia; imatinib; CGP74588; CYP3A
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-129678 (URN)10.1097/FTD.0000000000000268 (DOI)000376938000006 ()26693810 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Society; Medical Research Council of Southeast Sweden; Novartis

Available from: 2016-06-27 Created: 2016-06-23 Last updated: 2018-01-10
Skoglund, K., Boiso, S., Jönsson, J.-I., Vikingsson, S., Carlsson, B. & Green, H. (2014). Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line. Pharmacogenetics & Genomics, 24(1), 52-61
Open this publication in new window or tab >>Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line
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2014 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 24, no 1, p. 52-61Article in journal (Refereed) Published
Abstract [en]

ObjectiveThe tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (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].Materials and methodsABCG2 SNPs 34Ggreater thanA, 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, 1574Tgreater thanG, and 1582Ggreater thanA were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity.ResultsWild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity.ConclusionThese findings show that the ABCG2 SNPs 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.

Place, publisher, year, edition, pages
Lippincott, Williams andamp; Wilkins, 2014
Keywords
ABCG2; CGP74588; chronic myeloid leukemia; imatinib; N-desmethyl imatinib; pharmacogenetics; single-nucleotide polymorphism; tyrosine kinase inhibitor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-103285 (URN)10.1097/FPC.0000000000000022 (DOI)000328629800007 ()
Available from: 2014-01-17 Created: 2014-01-16 Last updated: 2017-12-06
Skoglund, K., Moreno, S. B., Baytar, M., Jönsson, J.-I. & Gréen, H. (2013). ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro. Pharmacogenomics and Personalized Medicine, 6, 63-72
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, p. 63-72Article 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
Skoglund, K. (2013). Influence of CYP3A enzymes and ABC transporters on the activity of tyrosine kinase inhibitors in chronic myeloid leukemia. (Doctoral dissertation). Linköping: Linköping University Electronic Press
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. p. 77
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1370
National Category
Medical and Health Sciences
Identifiers
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)
Opponent
Supervisors
Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2013-09-12Bibliographically approved
Fyrberg, A., Skoglund, K., Wolk, M. & Lotfi, K. (2012). A potential role of fetal hemoglobin in the development of multidrug resistance. Biochemical and Biophysical Research Communications - BBRC, 427(3), 456-460
Open this publication in new window or tab >>A potential role of fetal hemoglobin in the development of multidrug resistance
2012 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 427, no 3, p. 456-460Article in journal (Refereed) Published
Abstract [en]

Our previous data from a human leukemic cell line made resistant to the nucleoside analog (NA) 9-beta-D-arabinofuranosylguanine (AraG) revealed a massive upregulation of fetal hemoglobin (HbF) genes and the ABCB1 gene coding for the multidrug resistance P-glycoprotein (P-gp). The expression of these genes is regulated through the same mechanisms, with activation of the p38-MAPK pathway and inhibition of methylation making transcription factors more accessible to activate these genes. We could show that AraG, as well as other NAs, and P-gp substrates could induce global DNA demethylation and induction of Hb gamma and P-gp both at the mRNA and protein expression level. We speculate that the expression of HbF prior to drug exposure or in drug-resistant cell lines is a strategy of the cancer to gain more oxygen, and thereby survival benefits. We also believe that P-gp may be induced in order to excrete Hb degradation products from the cells that would otherwise be toxic. By using Hb gamma siRNA and pharmacological inhibitors of HbF production we here present a possible relationship between HbF induction and multi-drug resistance in a human leukemia cell line model.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Multi-drug resistance, Fetal hemoglobin, Demethylation, Nucleoside analog
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86656 (URN)10.1016/j.bbrc.2012.07.129 (DOI)000311263200004 ()
Note

Funding Agencies|Swedish Cancer Foundation||County Council of Ostergotland||AFA insurance||

Available from: 2012-12-20 Created: 2012-12-20 Last updated: 2017-12-06
Wennerstrand, P., Dametto, P., Hennig, J., Klingstedt, T., Skoglund, K., Lindqvist Appell, M. & Mårtensson, L.-G. (2012). Structural Characteristics Determine the Cause of the Low Enzyme Activity of Two Thiopurine S-Methyltransferase Allelic Variants: A Biophysical Characterization of TPMT*2 and TPMT*5. Biochemistry, 51(30), 5912-5920
Open this publication in new window or tab >>Structural Characteristics Determine the Cause of the Low Enzyme Activity of Two Thiopurine S-Methyltransferase Allelic Variants: A Biophysical Characterization of TPMT*2 and TPMT*5
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2012 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 51, no 30, p. 5912-5920Article in journal (Refereed) Published
Abstract [en]

The enzyme thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurine drugs used to treat acute lymphoblastic leukemia and inflammatory bowel disease. Thus far, at least 29 variants of the TPMT gene have been described, many of which encode proteins that have low enzyme activity and in some cases become more prone to aggregation and degradation. Here, the two naturally occurring variants, TPMT*2 (Ala80 → Pro) and TPMT*5 (Leu49 → Ser), were cloned and expressed in Escherichia coli. Far-UV circular dichroism spectroscopy showed that TPMT*2 was substantially destabilized whereas TPMT*5 showed much greater stability comparable to that of wild-type TPMT (TPMTwt). The extrinsic fluorescent molecule anilinonaphthalene sulfonate (ANS) was used to probe the tertiary structure during thermal denaturation. In contrast to TPMTwt, neither of the variants bound ANS to a large extent. To explore the morphology of the TPMT aggregates, we performed luminescent conjugated oligothiophene staining and showed fibril formation for TPMT*2 and TPMT*5. The differences in the flexibility of TPMTwt, TPMT*2, and TPMT*5 were evaluated in a limited proteolysis experiment to pinpoint stable regions. Even though there is only one amino acid difference between the analyzed TPMT variants, a clear disparity in the cleavage patterns was observed. TPMT*2 displays a protected region in the C-terminus, which differs from TPMTwt, whereas the protected regions in TPMT*5 are located mainly in the N-terminus close to the active site. In conclusion, this in vitro study, conducted to probe structural changes during unfolding of TPMT*2 and TPMT*5, demonstrates that the various causes of the low enzyme activity in vivo could be explained on a molecular level.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2012
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-80185 (URN)10.1021/bi300377d (DOI)000308262600005 ()
Note

funding agencies|Swedish Childhood Cancer Foundation||Swedish Research Council||EMBO||

Available from: 2012-08-22 Created: 2012-08-22 Last updated: 2017-12-07Bibliographically approved
Skoglund, K., Boiso Moreno, S., Jönsson, J.-I. & Green, H. (2011). Functional Characterization of ABCG2 Polymorphisms and Their Influence on Tyrosine Kinase Inhibitor Effects in Chronic Myeloid Leukemia Cells in BLOOD, vol 118, issue 21, pp 1491-1491. In: BLOOD. Paper presented at 53rd ASH Annual Meeting and Exposition (pp. 1491-1491). American Society of Hematology, 118(21)
Open this publication in new window or tab >>Functional Characterization of ABCG2 Polymorphisms and Their Influence on Tyrosine Kinase Inhibitor Effects in Chronic Myeloid Leukemia Cells in BLOOD, vol 118, issue 21, pp 1491-1491
2011 (English)In: BLOOD, American Society of Hematology , 2011, Vol. 118, no 21, p. 1491-1491Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
American Society of Hematology, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-75740 (URN)000299597105224 ()
Conference
53rd ASH Annual Meeting and Exposition
Available from: 2012-03-09 Created: 2012-03-09 Last updated: 2012-03-09
Coulthard, S. A., Redfern, C. P., Lindqvist Appell, M., Skoglund, K., Jakobsen Falk, I., Hall, A. G., . . . Hogarth, L. A. (2011). Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers. MOLECULAR CANCER THERAPEUTICS, 10(3), 495-504
Open this publication in new window or tab >>Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers
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2011 (English)In: MOLECULAR CANCER THERAPEUTICS, ISSN 1535-7163, Vol. 10, no 3, p. 495-504Article in journal (Refereed) Published
Abstract [en]

The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dG(s)) into the DNA of thiopurine-treated cells causes cell death, but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Because the growth of MTAP-deleted tumor cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP(-)) transfected to express MTAP constitutively (A549-MTAP(+)). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intracellularly to MeTIMP, was markedly higher in both cell lines under MTAP(-) conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dG(s) incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67042 (URN)10.1158/1535-7163.MCT-10-0798 (DOI)000288153900012 ()
Available from: 2011-03-25 Created: 2011-03-25 Last updated: 2014-01-09Bibliographically approved
Green, H., Skoglund, K., Rommel, F., Mirghani, R. A. & Lotfi, K. (2010). CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 66(4), 383-386
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, p. 383-386Article 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.

Keywords
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
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