Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers

Jiko, Mari; Yano, Ikuko; Sato, Eriko; Takahashi, Kunitaro; Motohashi, Hideyuki; Masuda, Satohiro; Okuda, Masahiro; Ito, Noriyuki; Nakamura, Eijiro; Segawa, Tomio; Ogawa, Osamu; Inui, Ken Ichi

doi:10.1007/s10147-007-0681-y

Cited by 23 publications

(11 citation statements)

References 31 publications

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“…Several studies have reported that gemcitabine activates nF-κB (13,14,16,20) and Mdr (27). our results also showed that gemcitabine enhanced nF-κB protein expression in both our pancreatic cancer cell lines.…”

Section: Discussionsupporting

confidence: 77%

Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

Liu

Chen²,

Tong³

et al. 2011

Mol Med Rep

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Abstract. Many studies have demonstrated that emodin inhibits the growth and induces the apoptosis and chemosensitization of various cancer cells in animal models. The aim of this study was to investigate the molecular mechanism of the chemo-sensitization potential of emodin on gemcitabine in pancreatic cancer cell lines via inhibition of nuclear factor-κB (nF-κB). SW1990 and SW1990/GZ cells were treated with: i) emodin (20 µmol/l), ii) nF-κB inhibitor Bay 11-7082 (5 µmol/l), iii) gemcitabine (20 µmol/l), iv) pretreated with emodin for 24 h followed by coincubation with gemcitabine for 24 h, or v) pre-treated with Bay 11-7082 for 1 h followed by treatment with gemcitabine for 24 h. SW1990 and SW1990/GZ cells were also treated with emodin (20, 40 and 80 µmol/l). cellular proliferation and apoptosis were detected by the Cell Counting Kit-8 (CCK-8) assay and flow cytometry. nF-κB protein was detected by Western blotting. SW1990/GZ cell morphological changes were observed under optical and fluorescence microscopes. Emodin strongly inhibited the proliferation and induced the apoptosis of both pancreatic cancer cell lines. Furthermore, emodin combined with gemcitabine induced a higher percentage of growth inhibition and apoptosis in both pancreatic cancer cell lines compared to gemcitabine alone. Pre-treatment of SW1990/ GZ cells with Bay 11-7082 for 1 h followed by gemcitabine resulted in greater inhibitory and apoptosis rates compared to gemcitabine alone. The resistant pancreatic cell line SW1990/ GZ presented higher constitutive nF-κB protein expression compared to the SW1990 cells. emodin not only downregulated nF-κB in a dose-dependent manner in SW1990 and SW1990/GZ cells under unstimulated conditions, but also inhibited gemcitabine-induced nF-κB protein expression. emodin potentiated the antitumor effects of gemcitabine in pancreatic cancer, which was related to the down-regulation of nF-κB.

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Section: Discussionsupporting

confidence: 77%

Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

Liu

Chen²,

Tong³

et al. 2011

Mol Med Rep

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“…Several studies have reported associations between the ABCB1 genotype and different kinetic parameters, such as the AUC [108] and the apparent total clearance after : increased, ; decreased, AEs adverse effects, AUC area under the concentration-time curve, AUC/D dose-dependent AUC, AUC x AUC from time 0 to time x, AUC x /D dose-dependent AUC x , C concentration, C x concentration at time x, C x /D dose-dependent C x , CL apparent total clearance after intravenous administration, CL/F apparent total clearance after oral administration, C max maximum concentration, C max /D dosedependent C max , D required dose, ER extraction rate, F bioavailability, NS not significant, t elimination half-life, t max time to attain C max a X denotes that this variant was tested [109,110] of paclitaxel, whereas other studies did not find any significant associations [111,112]. Two studies reported an association with survival in 43 Chinese gastric cancer patients [113] and in 109 Korean patients with metastatic breast cancer [114].…”

Section: Taxanesmentioning

confidence: 88%

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

et al. 2015

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ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

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“…The DOC AUC and CL have been reported, in most cases, to be unaffected by ABCB1 SNPs [63,64] but one study in 92 Caucasians patients reported a significantly decreased DOC CL only in ABCB1 1236TT homozygous (-25%) and no influence of 2677G>T/A and 3435C>T polymorphisms [65]. A weak association between PK parameters and ABCB1 genetic status has been also described for PAC [66][67][68]. For example, in the study of Nakajima et al, patients possessing the 3435T allele had a significantly higher AUC of 3'-phydroxyPAC (the main PAC metabolite) compared to those possessing the 3435C allele.…”

Section: Abcb1mentioning

confidence: 84%

Genetic Polymorphisms of ATP-Binding Cassette Transporters ABCB1 and ABCC2 and their Impact on Drug Disposition

Haufroid

2011

CDT

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The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that translocate a variety of substrates across extra- and intra-cellular membranes, and act as efflux proteins. ABC transporters are characterised by the presence of genetic polymorphisms mainly represented by single nucleotide polymorphisms (SNPs), some of which having an impact on their activity. Besides physiological substances, drugs are also substrates of some ABC transporters, mainly ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2. Identifying the impact of these polymorphisms on the pharmacokinetics (PK) of these drugs may have important clinical implications, certainly for those characterised by a narrow therapeutic index and significant inter- and intra-patient PK variability. This review focuses specifically on ABCB1 and ABCC2 and critically analyses important publications dealing with the influence of ABCB1 and/or ABCC2 polymorphisms on drug disposition in humans. For different reasons discussed in this paper, the effect of ABCB1 and/or ABCC2 polymorphisms on drug concentrations in blood is not always easy to interpret and to correlate with pharmacological effects. In contrast, intracellular or target tissue drug concentrations appear more directly influenced by these polymorphisms, as illustrated with intralymphocyte concentrations for immunosupressants and antiretrovirals or with cerebrospinal fluid (CSF) concentrations for antiepileptics and antidepressants. Further research on intracellular and/or target tissue drug concentrations are still needed to better characterise the PK-PG (pharmacogenetics) relationship involving ABC transporters.

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Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers

Abstract: The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.

Cited by 23 publications

References 31 publications

Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

Genetic Polymorphisms of ATP-Binding Cassette Transporters ABCB1 and ABCC2 and their Impact on Drug Disposition

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