Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

Marsh, Sharon; Somlo, George; Li, X; Frankel, Paul; King, Cristi R.; Shannon, William D.; McLeod, Howard L.; Synold, Timothy W.

doi:10.1038/sj.tpj.6500434

Cited by 89 publications

(67 citation statements)

References 37 publications

(48 reference statements)

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“…42 To our knowledge, this is the largest prospective study reporting this association. The results, however, are in somewhat contrast to Henningsson et al 43 who found no correlation between clearance and CYP2C8*3, CYP2C8*4 and ABCB1 C3435T in 97 patients (male and female) treated with paclitaxel (80-225 mg m -2 ) and Marsh et al 44 who found no correlation between clearance and CYP2C8*3, CYP2C8*4, ABCB1 C1236T and ABCB1 G2677T in 93 patients with breast cancer treated with 24-h paclitaxel infusion (575-775 mg m -2 ). This discrepancy can be explained by chance or: in case of the study by Henningsson et al, by gender in so far that Joerger et al 45 showed a 20% higher elimination of paclitaxel in males than in females, and in the case of the study by Marsh et al 46 by the nonlinear elimination of paclitaxel reported in the studied population.…”

Section: Discussioncontrasting

confidence: 68%

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

et al. 2010

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The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h -1 (range 176-726 l h -1 ). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P ¼ 0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P ¼ 0.04) and ABCC1 g.7356253C4G (P ¼ 0.04).

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Section: Discussioncontrasting

confidence: 68%

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

et al. 2010

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“…For paclitaxel, a model CYP2C8 substrate, a significantly reduced metabolic capacity relating to CYP2C8*3 was determined in several in vitro studies (Dai et al, 2001;Soyama et al, 2001;Bahadur et al, 2002). However, the presence of this allele could not explain the observed interindividual variability in paclitaxel pharmacokinetics in clinical studies (Henningsson et al, 2005;Marsh et al, 2007). On the other hand, increased catalytic activity in carriers of CYP2C8*3 was observed for the two oral antidiabetic agents rosiglitazone and pioglitazone (Kirchheiner et al, 2006;Aquilante et al, 2008;Tornio et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Effect of theCYP2C8Genotype on the Pharmacokinetics and Pharmacodynamics of Repaglinide

et al. 2011

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ABSTRACT:The pharmacokinetics of repaglinide shows pronounced interindividual variability, for which several reasons have been considered, including interactions with drugs inhibiting CYP2C8 and CYP2C8 genetic polymorphism. However, existing data on the role of genetic polymorphisms in repaglinide disposition are not fully consistent. We studied the effect of CYP2C8*3 on the pharmacokinetics and pharmacodynamics of repaglinide in 29 healthy whites carrying CYP2C8*3/*3 (n ‫؍‬ 4), CYP2C8*1/*3 (n ‫؍‬ 13), or CYP2C8*1/*1 (n ‫؍‬ 12). After administration of a single dose of 2 mg of repaglinide, blood was drawn for assessment of repaglinide pharmacokinetics and pharmacodynamics, and urine was collected to quantify the main repaglinide metabolites M1 and M4 up to 24 h postdose. Repaglinide and the metabolites were quantified by liquid chromatography-tandem mass spectrometry. Considering only the effect of CYP2C8*3, the mean (95% confidence interval) area under the time-concentration curve . In addition, for urinary metabolite excretion and pharmacodynamic parameters, i.e., mean and maximal changes in insulin and glucose concentration, no significant differences between CYP2C8 genotypes were observed. Likewise, no significant effects on the pharmacokinetics or pharmacodynamics were observed when AUC and C max of repaglinide were corrected for reported effects of the SLCO1B1 521T>C polymorphism or when both polymorphisms were tested in a two-way ANOVA. In conclusion, CYP2C8*3 does not seem to play an important role in the pharmacokinetics and pharmacodynamics of repaglinide given in a therapeutic dose.

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“…In summary, neurons conducting pain and touch sensations in the distal extremities are most vulnerable to taxanes, to other antitubulin agents, and to platinums (11). Pharmacogenomic studies are seeking to explain an individual susceptibility to severe taxane neuropathy (12)(13)(14)(15). The current analysis focuses on specific taxane clinical data on neuropathy from large randomized clinical trials.…”

Section: Description Of Taxane Neurotoxicitymentioning

confidence: 99%

Defining Risks of Taxane Neuropathy: Insights from Randomized Clinical Trials

Kudlowitz

2013

Clinical Cancer Research

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Sensory neuropathy is a common but difficult to quantify complication encountered during treatment of various cancers with taxane-containing regimens. Docetaxel, paclitaxel, and its nanoparticle albuminbound formulation have been extensively studied in randomized clinical trials comparing various dose and schedules for the treatment of breast, lung, and ovarian cancers. This review highlights differences in extent of severe neuropathies encountered in such randomized trials and seeks to draw conclusions in terms of known pharmacologic factors that may lead to neuropathy. This basic knowledge provides an essential background for exploring pharmacogenomic differences among patients in relation to their susceptibility of developing severe manifestations. In addition, the differences highlighted may lead to greater insight into drug and basic host factors (such as age, sex, and ethnicity) contributing to axonal injury from taxanes.

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Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

Cited by 89 publications

References 37 publications

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

Effect of theCYP2C8Genotype on the Pharmacokinetics and Pharmacodynamics of Repaglinide

Defining Risks of Taxane Neuropathy: Insights from Randomized Clinical Trials

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