Inhibition of etoposide elimination in the isolated perfused rat liver by Cremophor EL and Tween 80

Abstract

Cremophor EL, a surfactant used in the clinical formulation of cyclosporine and paclitaxel, will reverse the multidrug resistance (MDR) phenotype in vitro. As other MDR modulators can alter the pharmacokinetics of cytotoxic drugs, the aim of this study was to examine the effect of Cremophor and another MDR-reversing surfactant, Tween 80, on the hepatic elimination and biliary excretion of etoposide. Using the isolated perfused rat-liver model with 80 ml recirculating perfusate containing 20% red blood cells and 4% bovine serum albumin, etoposide (1.6 mg) with and without Cremophor (800 or 80 mg) or Tween 80 (80 mg) was given into the perfusate reservoir, and perfusate and bile samples were collected for 3 h. Etoposide was measured by high-performance liquid chromatography (HPLC) and Cremophor was measured using a bioassay. Both surfactants changed the etoposide elimination profile from biphasic to monophasic. High-dose Cremophor increased the AUC (from 334 +/- 23 to 1540 +/- 490 microgram min ml(-1), P<0.05) and decreased the total clearance (from 4.8 +/- 0.3 to 1.1 +/- 0.3 ml/min, P<0.05) and biliary clearance (from 2.6 +/- 1.1 to 0.5 +/- 0.2 ml/min, p<0.05) but decreased the elimination half-life (from 62 +/- 17 to 40 +/- 5 min, P<0.05) and volume of distribution (from 424 +/- 85 to 65 +/- 19 ml, P<0.05). Low-dose Cremophor and Tween 80 caused intermediate effects on these parameters that were statistically significant for total clearance, half-life, and volume of distribution. Cremophor had no adverse effect on liver function, whereas Tween 80 caused haemolysis and cholestasis. The initial high-dose Cremophor perfusate concentration was 0.8 mg/ml, which previous studies have shown to be clinically relevant and close to the optimal level for MDR reversal in vitro (1.0 mg/ml). Cremophor may be a clinically useful MDR modulator, but it may alter the pharmacokinetics of the cytotoxic drug.

Hepatotoxicity during rapid intravenous loading with amiodarone: Description of three cases and review of the literature*

“…On the other hand, centroacinar damage found in the liver biopsy of one patient reported to the Swiss Agency of Therapeutic Products and one of the case reports (27) does not support this possibility, because membrane permeabilization should affect particularly the peripheral parts of the liver lobules. Ex vivo, polysorbate 80 caused hemolysis and cholestasis in the isolated perfused rat liver (56), as well as reversible accumulation of fat in rat hepatocyte cell lines already within 3 hrs after exposure (57). In addition to its hepatotoxic effects, mild to moderate depression of the central nervous system after intraperitoneal or oral administration to rats and mice (58), and after intracerebroventricular injection in rats, convulsions were observed (59).…”

Impact of Dendrimers on Solubility of Hydrophobic Drug Molecules

“…The solubility of DTX in water is 3–5 μg/mL (Mathew et al, 1992; Ali et al, 1997; Zaske et al, 2001; Hamada et al, 2006; Du et al, 2007). The marketed formulation of DTX, Taxotere® is formulated with 13% of ethanol and polysorbate-80 and causes anaphylactic hypersensitivity, hemolysis and cholestasis (Weiss et al, 1990; Bissery et al, 1992; Ellis et al, 1996; Loos et al, 2003; Marupudi et al, 2007). Pooja et al used PAMAM with d-α-tocopherol-PEG-succinate (TPGS) mixed-micelles to improve the solubility of DTX.…”

“…Besides, PTX is found to be a substrate for p-glycoprotein and multidrug resistance protein-1 mediated efflux, and hence it has poor efficacy in cells which overexpress p-glycoprotein and multidrug resistance protein-1 (Hardman et al, 1996). PTX solubilizes in the water at a concentration of 0.35–0.7 μg/mL (Weiss et al, 1990; Bissery et al, 1992; Ellis et al, 1996; Loos et al, 2003; Marupudi et al, 2007). The marketed formulation of PTX (Taxol®) contains 50% polyoxyethylated castor oil and 50% ethanol to solubilize PTX but it exhibits many adverse effects such as hypersensitivity, gastrointestinal toxicity and neutropenia.…”

Comparative pharmacokinetic study of high-dose etoposide and etoposide phosphate in patients with lymphoid malignancy receiving autologous stem cell transplantation

“…In rodent models, polysorbate 80 has been shown to: (1) increase the volume of distribution of doxorubicin in plasma, 15 (2) to increase the blood barrier penetration of methotrexate 17 and (3) to directly inhibit E elimination from isolated perfused rat livers. 35 Polysorbate 80 also increases the killing by E of lung adenocarcinoma cells, presumably by surfactantenhanced cell membrane penetration. 36 In addition, polyethylene glycol 300 MW, another component in the E formulation, has been shown to increase the free fraction of highly bound drugs such as propanolol in the rat.…”