Effect of Cremophor EL on the pharmacokinetics, antitumor activity and toxicity of doxorubicin in mice

Differential alteration of cisplatin cytotoxicity and myelotoxicity by the paclitaxel vehicle cremophor EL

“…Values are means + SD of six mice (Ht hematocrit, WBC white blood cells, BUN blood urea nitrogen, SCr serum creatinine) Saline CR CDDP CDDP + CR Ht (%) 41 ±2.5 42 ±3.0 31 ±3.0* , ** 38 ±3.5*** WBC (10 -3 mm 3 ) 9.56±1.0 8.07±0.7 6.57±0.5* , ** 8.30±0.7*** BUN (mg/dl) 22 ±3.5 21 ±4.0 55 ±6.0* , ** 51 ±4.7* , ** SCr (mg/dl) 0.6 ±0.09 0.55±0.07 1.3 ±0.2* , ** 1.1 ±0.17* , ** * , ** , ***Significant difference from saline, CR or CDDP groups at P<0.05, respectively, using ANOVA followed by Tukey-Kramer multiple comparison test In vitro experiments showed that CR enhanced the cytotoxicity of CDDP against cultured EAC cells, an effect that was not associated with a parallel increase in CDDP cellular accumulation. This observation is in accordance with several studies demonstrating that CR can significantly enhance the cytotoxicity of doxorubicin (DOX; Badary et al 1998) and paclitaxel (Nygren et al 1995) in primary cultures of tumor cells. It could be suggested that CR makes tumor cells more vulnerable to the action of CDDP and hence enhances its cytotoxicity.…”

A comparison of commonly used polyethoxylated pharmaceutical excipients on their ability to inhibit P‐glycoprotein activity in vitro

“…37,38 The observation that many commonly used pharmaceutical excipients may inhibit P-gp activity in vitro has prompted the investigation of the effects of these excipients in various animal models. 31,39,40 Most of these studies have examined the effects of Cremophor EL in tumorbearing mouse models, but no identifiable trends have emerged. Woodcock et al reported that the mean survival time of mice is increased when Cremophor EL is included in the formulation of an anti-cancer drug.…”

“…For example, Badary et al 39 observed that the initial plasma concentration of doxorubicin (20 mg/kg), a P-gp substrate, 1 in female Swiss albino mice is much greater when Cremophor EL (2.5 mL/kg) is included in the formulation than when it is administered alone. 39 Badary et al concluded that addition of Cremophor EL to doxorubicin increased antitumor activity and cardiotoxicity as a result of enhanced bioavailability, which caused an overall decrease in mortality rates. 39 Badary et al also concluded that the exact mechanism for decreased doxorubicin-induced mortality in mice is not yet known.…”

“…39 Badary et al concluded that addition of Cremophor EL to doxorubicin increased antitumor activity and cardiotoxicity as a result of enhanced bioavailability, which caused an overall decrease in mortality rates. 39 Badary et al also concluded that the exact mechanism for decreased doxorubicin-induced mortality in mice is not yet known. 39 Additional experiments (e.g., gut perfusion studies in rats, pharmacokinetic studies in animals) should be performed in vivo to further characterize the effects of commonly used polyethoxylated pharmaceutical excipients on P-gp activity.…”

“…39 Badary et al also concluded that the exact mechanism for decreased doxorubicin-induced mortality in mice is not yet known. 39 Additional experiments (e.g., gut perfusion studies in rats, pharmacokinetic studies in animals) should be performed in vivo to further characterize the effects of commonly used polyethoxylated pharmaceutical excipients on P-gp activity. Such inhibition of P-gp activity in vivo could cause drug-drug interactions, alter the pharmacokinetic profiles of drugs that are P-gp substrates, and increase toxicity.…”