Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib

Gardner, Erin R.; Burger, Herman; vanSchaik, R.H.N.; VanOosterom, A.T.; DeBruijn, E A; Guetens, Gunther; Prenen, Hans; Dejong, F; Baker, Sharyn D.; Bates, Susan E.

doi:10.1016/j.clpt.2006.05.003

Cited by 133 publications

(97 citation statements)

References 36 publications

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“…The reduced protein levels and altered ATPase activity of the BCRP C421A variant might affect the oral absorption and/or elimination pathways of gefitinib and thereby increase the steady-state gefitinib plasma concentrations leading to diarrhoea. In contrast, Gardner et al (2006) did not find significant differences in the pharmacokinetic parameters of imatinib in vivo between 16 patients heterozygous for the C421A SNP compared with 66 patients harbouring the wild-type sequence. This result was unexpected, since the authors showed that HEK293 cells transfected with wild-type BCRP accumulated significantly less imatinib than HEK293 cells transfected with the C421A BCRP variant, despite similar levels of protein expression.…”

Section: Bcrp Variantscontrasting

confidence: 59%

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

2008

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Section: Bcrp Variantscontrasting

confidence: 59%

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

2008

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“…An initial study of 9 allelic variants in 82 patients found no correlation between polymorphisms in ABCB1, ABCG2, CYP2C9, CYP2C19 or CYP3A4 and imatinib clearance at steady-state. 20 However, a smaller subsequent study found a correlation between ABCB1 polymorphisms and steadystate clearance of imatinib. 21 In direct contradiction to the findings of Judson et al, in this study, an overall decrease in clearance was observed, from day 1 to steady-state.…”

Section: Discussionmentioning

confidence: 99%

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Gardner

Sparreboom²,

Verweij³

et al. 2008

Cancer Biology & Therapy

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This manuscript has been published online, prior to printing.Once the issue is complete and page numbers have been assigned, the citation will change accordingly.Purpose: Chronic imatinib exposure has been shown to result in upregulation of the ABCB1 (P-glycoprotein) and ABCG2 (BCRP) transporters in vitro, for which imatinib is a substrate. This finding, along a trend towards increasing imatinib clearance over time in patients, has resulted in the suggestion that pharmacokinetic resistance may be contributing to eventual treatment failure. Here, we sought to determine the effects of long-term imatinib exposure on apparent oral clearance and transporter expression in vivo.Results: Plasma and liver concentrations of imatinib did not change significantly (p > 0.1) over the course of treatment, suggesting that steady-state had been reached. There was no increase in Abcb1 or Abcg2 expression in liver samples, whereas expression of these transporters in intestinal samples was highly variable, and no increase was apparent.Methods: Male BALB/c mice were treated daily-times 5 with oral imatinib at a dose of 50 mg/kg for 4 consecutive weeks. Imatinib concentrations were measured in plasma and liver tissue prior to treatment and following each week of dosing. Western blotting of liver and intestinal tissue lysates was performed to assess expression of Abcb1 and Abcg2.Conclusions: Imatinib does not appear to cause upregulation of ABC transporters in the hepatic and intestinal compartments in mice. These data do not support the possibility that autoinduction contributes to the development of resistance to imatinib.

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“…16 Previous studies have investigated whether SNPs in ABCB1, including 1236T4C, 2677G4T/A and 3435T4C, affect IM pharmacokinetics; however, the role of ABCB1 genetic variation in IM trough concentration is still unclear. 17,18 OCT1, which is encoded by SLC22A1, is primarily expressed on hepatocytes, suggesting that it has a role in substrate uptake into the liver. [19][20][21] Although IM is a substrate of OCT1, 15,22,23 no association between IM and SLC22A1 286C4T or 1498G4A, variants not common in the Japanese population, was previously observed.…”

Section: Introductionmentioning

confidence: 99%

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

et al. 2010

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Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P¼0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P¼0.015). Moreover, previous studies have shown that the ABCG2 421C4A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C4A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.

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Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib

Cited by 133 publications

References 36 publications

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

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