Quantitative analysis of docetaxel in human plasma using liquid chromatography coupled with tandem mass spectrometry

Kuppens, I. E. L. M.; Maanen, Maria J. van; Rosing, Hilde; Schellens, Jan H.M.; Beijnen, J. H.

doi:10.1002/bmc.457

Cited by 52 publications

(33 citation statements)

References 17 publications

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“…Docetaxel concentrations in plasma samples were determined using a previously described sensitive and specific liquid chromatography-tandem mass spectrometry assay (19). Feces and urine samples were processed using liquid-liquid and solid-phase extraction followed by reverse-phase high-performance liquid chromatography with UV detection (4,18).…”

Section: Methodsmentioning

confidence: 99%

Absence of Both Cytochrome P450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

et al. 2009

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Docetaxel is one of the most widely used anticancer drugs. A major problem with docetaxel treatment, however, is the considerable interpatient variability in docetaxel exposure. Another disadvantage of the drug is that it has a very low oral bioavailability and can therefore only be administered i.v. The drug-metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug transporter P-glycoprotein (P-gp; MDR1) are considered to be major determinants of docetaxel pharmacokinetics. It has been hypothesized that CYP3A and P-gp work synergistically in limiting the systemic exposure to many orally ingested drugs. However, it has been difficult to examine this interplay in vivo. We therefore generated mice lacking all CYP3A and P-gp genes. Although missing two primary detoxification systems, Cyp3a/Mdr1a/1b

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Section: Methodsmentioning

confidence: 99%

Absence of Both Cytochrome P450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

et al. 2009

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“…Blood samples were centrifuged, plasma was separated, and samples were immediately stored at À20jC until analysis. Docetaxel concentrations were determined with a validated liquid chromatography-tandem mass spectrometry assay earlier described (13). The validated range of docetaxel concentrations was 0.25 to 1,000 ng/mL and interassay accuracy and precision were between À10.2% and 1.02% and <12.8%, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…To investigate whether the relationship between genotype and the pharmacokinetics remained significant after inclusion of known determinants of docetaxel clearance, the model previously described by Bruno et al (19) was applied to our data set. In this model, the following relationship between clearance and covariates was found: 13 HEPÞ ðCÞ where body surface area (BSA), a 1 -acid glycoprotein (AAG), age (AGE), albumin (ALB), and hepatic function (HEP; i.e., aspartate aminotransferase and alkaline phosphatase, >60 IU and >300 IU, respectively) were the main predictors of docetaxel clearance.…”

Section: Methodsmentioning

confidence: 99%

Pharmacogenetic Screening of CYP3A and ABCB1 in Relation to Population Pharmacokinetics of Docetaxel

Bosch

Huitema

Doodeman

et al. 2006

Clinical Cancer Research

117

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Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel. Experimental Design: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling. Results: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A threecompartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (À25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1and the pharmacokinetics could be identified. Conclusions: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.The anticancer drug docetaxel (Taxotere) is approved for the treatment of patients with early-stage, locally advanced and/or metastatic breast cancer, non -small-cell lung cancer, and androgen-independent metastatic prostate cancer. The recommended dose ranges from 75 to 100 mg/m 2 given as a 1-hour infusion once every 3 weeks. An important limitation associated with docetaxel use is the unpredictable interindividual variability in efficacy and toxicity. Potential causes for such variability in drug effects include the pathogenesis and severity of the disease being treated, the occurrence of unintended drug interactions, and impairment of hepatic and renal function (1). Despite the potential importance of these clinical variables in determining drug effects, it is recognized that inherited differences in metabolism and excretion can have an even greater effect on the efficacy and toxicity of drugs (1).The metabolism of docetaxel consists of a CYP3A-mediated oxidation of the tert-butylpropionate side chain, which results in the formation of four metabolites with reduced cytotoxic activity (2). The elimination pathway is mediated by the membrane-localized, energy-dependent drug efflux ABC tran...

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“…were immediately stored at -20jC until analysis. Docetaxel and ritonavir concentrations in plasma were determined with the use of validated liquid chromatography coupled with tandem mass spectrometry methods (19,20). Pharmacokinetic and statistical analysis.…”

Section: Translational Relevancementioning

confidence: 99%

Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors

Oostendorp

Huitema²,

Rosing³

et al. 2009

Clinical Cancer Research

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Purpose: To enhance the systemic exposure to oral docetaxel by coadministration of ritonavir, an efficacious inhibitor of CYP 3A4 with minor P-glycoprotein inhibiting effects, in patients with cancer. Experimental Design: A proof-of-concept study was carried out in 12 patients with solid tumors. The first cohort of patients (n = 4) received 10 mg and the subsequent cohort (n = 8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized simultaneously or ritonavir given 60 minutes before docetaxel on days 1and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel. Results:The area under the plasma concentration-time curve in patients who received10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The area under the plasma concentration-time curve in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 F 1.5 and 2.8 F 1.4 mg/h/L, respectively, compared with 1.9 F 0.4 mg/h/L after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 131% F 90% and 161% F 91%, respectively. The oral combination of docetaxel and ritonavir was well tolerated. Conclusion: Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. These data are promising and form the basis for further development of a clinically applicable oral formulation of docetaxel combined with ritonavir.

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Quantitative analysis of docetaxel in human plasma using liquid chromatography coupled with tandem mass spectrometry

Cited by 52 publications

References 17 publications

Absence of Both Cytochrome P450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

Absence of Both Cytochrome P450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

Pharmacogenetic Screening of CYP3A and ABCB1 in Relation to Population Pharmacokinetics of Docetaxel

Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors

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