Pharmacokinetics of high dose etoposide (VP 16–213)

Holthuis, J.J.M.; Postmus, Pieter E.; Oort, W. J. van; Hulshoff, Bram; Verleun, H; Sleijfer, Dirk; Mulder, Nanno

doi:10.1016/0277-5379(86)90315-9

Cited by 50 publications

(12 citation statements)

References 13 publications

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“…Conjugation of etoposide to glucuronic acid plays a major role in its elimination in humans, rats, and rabbits (13,17,18). We therefore determined the etoposide glucuronide concentrations in plasma after i.v.…”

Section: Resultsmentioning

confidence: 99%

“…Effect of Abcc2 and P-gp on the urinary and fecal excretion of etoposide and its glucuronide. In humans, rats, and rabbits, elimination of etoposide mainly occurs via urinary excretion of unchanged etoposide and etoposide glucuronide (13,17,18). Because P-gp and Abcc2 markedly affected the plasma pharmacokinetics of etoposide and its glucuronide, we next assessed the overall excretion of these compounds in the same panel of knockout mice.…”

Section: Resultsmentioning

confidence: 99%

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P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide

Lagas

Fan

Wagenaar

et al. 2010

Clinical Cancer Research

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Purpose: Despite the extensive use of etoposide for the treatment of different malignant neoplasms, its main pharmacokinetic determinants are not completely defined. We aimed to study the impact of P-glycoprotein (P-gp/ABCB1) and the multidrug resistance proteins ABCC2 (MRP2) and ABCC3 (MRP3) on the pharmacokinetics of etoposide.Experimental Design: Abcb1a/1b, Abcc3 -/-, Abcb1a/1b;Abcc2 -/-, and Abcc2;Abcc3 -/-mice were used to investigate the separate and combined impact of P-gp, Abcc2, and Abcc3 on the in vivo behavior of etoposide.Results: P-gp restricted the oral (re)uptake of unchanged etoposide, and mediated its excretion across the gut wall. In contrast, hepatobiliary excretion was almost entirely dependent on Abcc2. Yet, complete loss of Abcc2 did not result in elevated liver or plasma concentrations of etoposide. Instead, Abcc2 -/-mice displayed an increased hepatic formation of etoposide glucuronide, which was secreted via Abcc3 from the liver to the blood circulation and eliminated with the urine. Combination Abcc2;Abcc3 -/-mice had highly increased accumulation of etoposide glucuronide in their livers, whereas both single knockouts did not, indicating that Abcc2 and Abcc3 provide alternative pathways for the hepatic elimination of etoposide glucuronide.Conclusions: P-gp, ABCC2, and ABCC3 significantly affect the pharmacokinetics of etoposide and/or etoposide glucuronide. Variation in transporter expression or activity may explain the high variation in oral availability of etoposide (25-80%) among cancer patients. However, despite the fact that substantial variations in transporter activity can occur, we believe that cancer patients are often relatively protected from etoposide toxicity due to overlapping functions of these transporters in the elimination of etoposide. Clin Cancer Res; 16(1); 130-40. ©2010 AACR.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide

Lagas

Fan

Wagenaar

et al. 2010

Clinical Cancer Research

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“…The inset in Fig. 5 shows the linear increase in current of the oxidation peaks at various ETO concentrations, with a sensitivity of 0.15±0.04 mA/mM· cm 2 and a LOD of 4±1 µM, which fits ETO therapeutic range (33.9-101.9, [27]). These results prove that the sensing platform is capable to monitor drugs and metabolites within their therapeutic or physiological ranges.…”

Section: A Measurements Of Metabolites and Anti-cancer Drugsmentioning

confidence: 83%

Electrochemical biochip for applications to wireless and batteryless monitoring of free-moving mice

Baj-Rossi

Micheli

Carrara

2014

2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society

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Abstract-A multi-sensing platform for applications in wireless and batteryless monitoring of free-moving small animals is presented in this paper. The proposed platform hosts six sensors: four biosensors for sensing of both disease biomarkers and therapeutic compounds, and two further sensors (T and pH) for biosensor calibration. Electrodeposition of Multi-Walled Carbon Nanotubes (MWCNTs) and the subsequent functionalization with proper enzymes is used to assure sensitivity and specificity in electrochemical biosensing. The realized sensors are demonstrated to be capable of measuring several parameters: lactate with a sensitivity of 77±26 µA/mM· cm 2 and a limit of detection (LOD) of 4±1 µM; glucose with a sensitivity of 63±15 µA/mM· cm 2 and a LOD of 8±2 µM; Etoposide (a well known anti-cancer agent) with a sensitivity of 0.15±0.04 mA/mM· cm 2 and a LOD of 4±1 µM; Open Circuit Potential (OCP) measurements are used on a Pt/IrOx junction to sense pH with a sensitivity of around -75±5mV/pH; while a Pt resistive thermal device is used to measure physiological temperature-range with an average sensitivity of 0.108±0.001 kΩ/°C.

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“…However, variation between patients was seen, as shown in other studies of both high and low dose etoposide (3, 6, 16). Comparison of the PPLs is difficult in view of the range of infusion times for both high and low dose studies in the literature, and AUC values published range from 68.4 pg/mlh for a low dose of 100 mg/m2 (5) to 2 800 pg/ml/h for a dose of 2.5 g/m2 (14).…”

Section: Discussionmentioning

confidence: 99%

“…The total area under the curve (AUC) was calculated using the trapezoidal method from time zero to the last measured concentration (14).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Study of High Dose Etoposide Infusion in Patients with Small Cell Lung Cancer

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Pharmacokinetics of high dose etoposide (VP 16–213)

Cited by 50 publications

References 13 publications

P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide

P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide

Electrochemical biochip for applications to wireless and batteryless monitoring of free-moving mice

Pharmacokinetic Study of High Dose Etoposide Infusion in Patients with Small Cell Lung Cancer

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