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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(-/-), Abcc2(-/-), 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.

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Etoposide phosphate and methotrexate are important anti-tumor chemotherapeutic agents. Our previously presented capillary zone electrophoresis (CZE) method using a high sensitivity cell (Z-cell) for quantitative analysis in biological media (urine, plasma) showed good precision and accuracy. The present results show that the investigation using a capillary with high sensitivity cell led to an approximately 10-fold improvement of the detection limit compared to standard capillaries. Plasma and urine samples were analyzed by using a calibration curve for drug concentrations between 0.1 and 100 microg/mL. Good detection limits and good relative standard deviations of the migration times and of the peak areas were observed in these experiments.

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In this study, P-glycoprotein modulator effects on pharmacokinetics and central nervous system distribution of the chemotherapeutic agent etoposide were evaluated. The multidrug resistance transporter P-glycoprotein is expressed in normal tissues, and its physiological function is thought to be an excretory and/or protective one. To examine this further, we evaluated etoposide under steady-state and bolus dose conditions. In microdialysis infusion studies, etoposide 15 mg/kg/hr was administered to 12 rats. Rats received sodium cyanide (1 or 100 mM), trifluoperazine (30 mM) or cyclosporine (4.14 mM) via microdialysis probe at 3.5 hr after etoposide infusion initiation. High-dose sodium cyanide (100 mM) increased the etoposide BBR,corr from 0.09 +/- 0.03 to 0.85 +/- 0.35. Similarly, trifluoperazine significantly increased the BBR,corr (0.05 +/- 0.02 vs. 1.30 +/- 0.43), whereas cyclosporine had no effect. In bolus studies, etoposide (10-12 mg/kg) was given alone or concomitant to cyclosporine (5 mg/kg) or tamoxifen (13.5 mg/kg). Control etoposide total systemic clearance (ml/min/kg) was 29.3 +/- 13.0 vs. 16.0 +/- 1.9 and 22.6 +/- 5.3 for cyclosporine and tamoxifen treatments, respectively. Etoposide nonrenal clearance (ml/min/kg) values for cyclosporine (12.0 +/- 1.6) and tamoxifen (18.1 +/- 3.6) treatments was also decreased from controls (23.5 +/- 10.5). Etoposide renal clearance (ml/min/kg) values (5.7 +/- 2.5) were not significantly different from cyclosporine (4.0 +/- 0.7) or tamoxifen (4.6 +/- 1.7) treatments, respectively. In this study, the ability of sodium cyanide and trifluoperazine to alter etoposide BBR,corr, demonstrated that etoposide distribution into brain is partly controlled by an active transport process. Similarly, the results indicate cyclosporine inhibits etoposide transport at the canalicular membrane and/or etoposide P-450 metabolism.

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A high-performance liquid chromatographic method was developed for the determination of a new podophyllotoxin derivative, TOP-53 (I), and TOP-53 glucuronide (II) as its major metabolite in rat plasma and urine. For the analysis of I, the sample was chromatographed on a reversed-phase C18 column with electrochemical detection after consecutive two-step liquid-liquid extractions. Compound II was determined as I after enzymatic hydrolysis of II. This method was validated sufficiently with respect to specificity, accuracy, and precision. The limits of quantitation for both I and II were 2 ng/ml in plasma and 10 ng/ml in urine. The method is thus useful for the pharmacokinetic study of I.

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PURPOSE: The objectives of this study were to determine etoposide pharmacokinetics after both acute and chronic exposure to cisplatin and to evaluate the relationship between etoposide systemic exposure and toxicity in children with neuroblastoma. PATIENTS AND METHODS: Seventeen children with newly diagnosed stage C or D neuroblastoma were given continuous infusions of 780 mg/m2 etoposide over 72 hours as part of multiagent chemotherapy. Etoposide pharmacokinetic parameters were estimated on three occasions in each patient: (1) 21 days after the first cisplatin dose (etoposide was given immediately after cyclophosphamide; cumulative cisplatin dose, 90 mg/m2), (2) 2 days after the third cisplatin dose (cumulative cisplatin dose, 270 mg/m2), and (3) 21 days after the final cisplatin dose (etoposide again immediately after cyclophosphamide; cumulative cisplatin dose, 360 mg/m2). Toxicity was scored on the basis of transfusion requirements and need for hospitalization. RESULTS: Etoposide systemic clearance decreased acutely when administered 2 days after cisplatin (median of 15.5 ml/min/m2) compared with both the first study (20.0 ml/min/m2) and the third study (19.7 ml/min/m2; p < 0.001). The decrease in clearance resulted in a median 31% increase in etoposide area under the concentration-time curve (AUC) compared with the first study and a 36% increase compared with the third study. Toxicity scores were higher after the second study than after the first or third study (p = 0.01), and etoposide AUC was significantly correlated with toxicity score (p = 0.006). Neither etoposide renal clearance nor catechol excretion differed significantly among the courses. CONCLUSION: There was an acute decrease in etoposide systemic clearance when etoposide immediately followed cisplatin. No persistent decrease in etoposide clearance was noted after a cumulative dose of 360 mg/m2 cisplatin. Etoposide AUC was positively correlated with toxicity in a multidrug regimen.

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The kinetics and urinary excretion of etoposide and etoposide glucuronide were determined in 11 patients with obstructive jaundice (bilirubin greater than 2.0 mg/dL) and in 23 patients with normal renal and hepatic function. Mean (+/- SE) measurements of clearance (24.5 +/- 2.06 v 26.5 +/- 2.05 mL/min/m2), half-life (5.7 +/- 0.5 v 6.4 +/- 0.5 hours), and volume of distribution (12.4 +/- 1.1 v 13.7 +/- 1.6 L/m2) were not significantly different in patients with jaundice when compared with controls. Similarly, etoposide kinetics in three patients determined during a period of hyperbilirubinemia were not different from measurements made in the same patients following resolution of their obstructive jaundice. In patients with jaundice, 46% of an administered etoposide dose was excreted in the urine as etoposide compared with 35% in controls (P = .15). Urinary excretion of etoposide glucuronide accounted for 29% of an administered etoposide dose in control patients and 15% in those with hepatic obstruction (P = .03). Biliary etoposide excretion measured in four patients with T-tubes was insignificant (less than 2.0% of an administered dose). The calculated renal clearance of etoposide was 11.5 mL/min/m2 in patients with jaundice and 10.4 mL/min/m2 in controls (P = .53). Respective metabolic clearance was 4.9 and 6.9 mL/min/m2 in these two study groups (P = .13). Although hepatic metabolism of etoposide may be slightly decreased in patients with obstructive jaundice, a modest increase in renal etoposide excretion appears to compensate for this change, so that total clearance is similar in the patients with jaundice when compared with controls. No etoposide dose reductions appear to be needed in treating patients with obstructive jaundice who have normal renal function.

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A highly sensitive enzyme-linked immunosorbent assay (ELISA) for etoposide (EP) was developed, which is capable of accurately measuring as little as 40 pg EP/ml. Anti-EP sera were obtained by immunizing rabbits with EP conjugated with mercaptosuccinyl bovine serum albumin (MS.BSA) using N-[beta-(4-diazophenyl)ethyl]maleimide (DPEM) as a heterobifunctional coupling agent. An enzyme marker was similarly prepared by coupling EP with beta-D-galactosidase (beta-Gal; EC 3.2.23) via DPEM. This ELISA was specific for EP and showed a very slight cross-reactivity with its major metabolite, cis-hydroxy acid of EP (0.91%), but none with 4'-demethylepipodophyllotoxin and drugs commonly used with EP in combination chemotherapy for cancer treatment. The values for EP concentration detected by this assay were comparable with those detected by the high-performance liquid chromatography (HPLC) method. However, the ELISA was about 1,250 times more sensitive in detecting EP at lower concentrations. Using this assay, drug levels were easily determined in the blood and urine of rats for 7 h after i.v. administration of EP at a single dose of 3 mg/kg. Due to its sensitivity and specificity for EP, the ELISA should prove to be a valuable new tool for use in clinical pharmacological studies.

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The bioavailability of orally administered etoposide varies considerably. The effect of dose on bioavailability has not previously been investigated. In this study six patients were each treated with oral etoposide at doses of 200, 400, and 600 mg, and the pharmacokinetics determined. Each patient acted as his own control. The area under the plasma concentration-time curve (AUC) was proportionately greatest at the lowest dose. Doubling the dose from 200 mg to 400 mg increased AUC by only 50%, and a further increase of only 2.2% occurred at a dose of 600 mg. These data show nonlinear bioavailability of etoposide within the range in clinical use and may explain the variable results of reported studies. The data may have important implications for chemotherapy regimens with oral etoposide.

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Drug monitoring is performed by means of sample extraction, sample purification by high-performance liquid chromatography (HPLC), and sample detection by time-of-flight mass spectrometry. This mass spectrometry utilizing 252Cf fission fragment-induced ionization and desorption of nonvolatile compounds is suitable as a universal, nondestructive detector in HPLC. Liquid chromatography and mass spectrometry are combined, so that mass analysis can be operated online and offline to the fractional sampling of the effluent and the samples can still be recovered. As an alternative to HPLC separation, samples can be purified by thin-layer chromatography (TLC), resulting an offline TLC + MS combination. Preliminary pharmacokinetic data for etoposide (VP16-213) together with calibration data are presented, and are discussed with reference to the sensitivity and detection limit of the new experimental method.

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