Semi-physiologically based pharmacokinetic modeling of paclitaxel metabolism and in silico-based study of the dynamic sensitivities in pathway kinetics

Fransson, Moa; Brugård, Jan; Aronsson, Peter; Gréen, Henrik

doi:10.1016/j.ejps.2012.08.002

Cited by 3 publications

(2 citation statements)

References 28 publications

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“…On the contrary, there was no significant association observed between the ABCB1 G2677T/A polymorphism and hematologic or nonhematologic paclitaxel toxicity in metastatic breast cancer patients [44]. A study by Fransson and coworkers revealed that SNPs causing changes in metabolism or transport had a minimal effect on the plasma concentration of paclitaxel; however, its main metabolite (6a-hydroxypaclitaxel) may be affected by even small changes in the capacity of transport or metabolism [45]. This study proposes that genetic polymorphisms may play an important role for individualizing paclitaxel treatment [45].…”

Section: Abcb1mentioning

confidence: 99%

Pharmacogenetics of Taxanes: Impact of Gene Polymorphisms of Drug Transporters on Pharmacokinetics and Toxicity

et al. 2012

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Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

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Section: Abcb1mentioning

confidence: 99%

Pharmacogenetics of Taxanes: Impact of Gene Polymorphisms of Drug Transporters on Pharmacokinetics and Toxicity

et al. 2012

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“…Lal et al 10 found that the clearance rate of paclitaxel in CC-GG-CC wild-type patients with C1236T, G2677T/ A, and C3435T mutations was significantly increased compared with CT-GT-CT and TT-TT-TT mutants, while the plasma peak drug concentration was significantly decreased. Conversely, Fransson et al 11 reported that SNPs have only a small influence on the plasma concentration of paclitaxel, but that even a slight change of transfer or metabolism would affect the concentration of the main metabolic products of paclitaxel. The effect of ABCB1 on drug toxicity is therefore of greater importance than the pharmacokinetics of the drug itself.…”

Section: Introductionmentioning

confidence: 98%

The ABCB1 3435C > T polymorphism influences docetaxel transportation in ovarian cancer

et al. 2019

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Objective To investigate the effect of the ATP-binding cassette transporter superfamily B member 1 gene ( ABCB1) 3435C > T single nucleotide polymorphism (SNP) on docetaxel transportation in ovarian cancer cells. Methods ES-2 and SKOV3 cells were transfected with an ABCB1 3435C > T recombinant plasmid, and mRNA expression was detected by real-time PCR. The MTT assay was used to detect the toxicity of docetaxel. High-performance liquid chromatography determined the drug concentration in different cell models to evaluate intracellular accumulation, and a transmembrane resistance experiment was used to assess permeability and evaluate the effect of P-gp activity on drug transportation. A tumor-bearing mouse model was established to evaluate the effect of ABCB1 3435C > T on docetaxel resistance. Results P-gp was overexpressed in cells transfected with the ABCB1 3435C > T plasmid, leading to a significant increase in drug resistance to docetaxel. ABCB1 3435C/wild-type transfection significantly promoted the transport of docetaxel mediated by P-gp compared with ABCB1 3435T/mutant transfection. Conclusion P-gp encoded by the ABCB1 variant allele appears to be more efficient at transporting docetaxel compared with the wild-type allele. The ABCB1 3435C > T SNP dramatically affected the efflux ability of P-gp against docetaxel, and may influence P-gp expression and activity.

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Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity

Wozniak

Vornov

et al. 2016

Cancer Research

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Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities of certain drugs are unclear. At their maximal tolerated doses (MTD), the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a two week MTD-dosing regimen followed by a determination of drug pharmacokinetics, tissue distribution and multiple functional measures of peripheral nerve toxicity for four weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity produced biologically was consistently more severe with paclitaxel. Overall, our results argued that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity.

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Semi-physiologically based pharmacokinetic modeling of paclitaxel metabolism and in silico-based study of the dynamic sensitivities in pathway kinetics

Cited by 3 publications

References 28 publications

Pharmacogenetics of Taxanes: Impact of Gene Polymorphisms of Drug Transporters on Pharmacokinetics and Toxicity

Pharmacogenetics of Taxanes: Impact of Gene Polymorphisms of Drug Transporters on Pharmacokinetics and Toxicity

The ABCB1 3435C > T polymorphism influences docetaxel transportation in ovarian cancer

Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity

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