Effect of P-glycoprotien blockers on the bioavailability of paclitaxel in swiss albino mice

In this study, we have investigated the influence of P-glycoprotein blockers, namely verapamil and cyclosporine on the oral bioavailability of anticancer paclitaxel, aiming for increasing the oral bioavailability of paclitaxel with possibly reducing its side effect resulting from its parentral administration. The oral bioavailability of paclitaxel [10 mg/kg] in Swiss albino mice pretreated with either verapamil [20 mg/kg] and/or cyclosporine [50 mg/kg] was enhanced by 2.7 and 5.7 fold, respectively. This result may show that both drugs effectively inhibited the P-glycoprotein effhix pump activity in the intestinal tract, allowing for better absorption of paclitaxel. In this context art indirect index of P-glycoprotein efflux activity was used where a certain dye Rh-123 is transported by the membrane efflux P-glycoprotein pump in the same way as paclitaxel. The dye has a certain fluorescence which can be measured spectroflurometrically and its content in the intestinal tissue would reflect the amount absorbed as a result of P-glycoprotein inhibition. This study showed that Rh-123 was alike in the groups of control, i.p., and p.o. of paclitaxel. Pretreatment of oral paclitaxel with either cyclosporine an/or verapamil showed 2 and 1.4 times increase in Rh-123 level, respectively, indicating that cyclosporine was more effective than verapamil in inhibiting P-glycoprotein efflux pump activity. Paclitaxel itself had no effect on the leukocyte count but prior administration of either cyclosporine or verapamil significantly decreased the total number of white blood cells. Cyclosporine seemed to have a greater deleterious effect than verapamil. Both verapamil and cyclosporine given with oral paclitaxel also induced marked rise in the cardiac enzyme CK-MB but the effect was only transient and subsided after 48 hours, this has also been histopathologically confirmed. On the other hand, survival data of Ehrlich carcinoma bearing mice treated with pacliaiel indicated that both P-glycoprotein blockers did not adversely affect the antitumor activity of paclitaxel. Further work would certainly be needed for setting the benefit/risk ratio before the use of Pglycoprotein blockers can be advocated clinically

Effect of glutamine on cisplatin-induced nephrotoxicity and antitumor efficacy in mice

Nephrotoxicity is a dose-limiting factor in clinical use of cisplatin.This study aimed at investigating the protective role of two g1utamine[31n] doses against cisplaun-imlucecI nephrotoxictty in normal mice, and investigating their effect on the antitumor efficacy of ciplatin in mice bearing Ehrlich ascites carcinoma[EAC]. Experiment 1: 60 female albino mice were divided into 6 groups, 10 mice each. The first group received a single i.p. injection with normal saline and served as control. The second group received a single i.p.5 mg/kg body weigt cisplatin injection. The third and fourth groups received oral doses of glutamine 150 and 300mg/kg body weight respectively. The fifth and sixth groups received oral glutamine doses as the third and fourth groups one hour prior to Cs injection respectively. Animals were sacrified 7days after cisplatin injection, sera were collected and kidney were surgically removed and 10% homogenates were prepared for detection of creatinine level, malondialdehyde[MDA], reduced glutathione level[GSH], and glutathione peroxidase[GSH-Px].Experiment II for investigating antitumor efficacy, 60 mice bearing i.p. EAC, were treated as mentioned in experiment I The mean survival time was determined. Experiment III, the effect of such treatments on tumor growth delay was also assessed in 60 mice bearing s.c. EAC. Cisplatin injection alone induced a significant increase in serum creatinine, renal MDA, decrease of GSH levels and GSH-Px activity. Histological examination confirmed renal damage. Pretreatment with glutamine significantly attenuated the disturbance induced by cisplatin in creatinine, MDA, GSH levels, GSH-Px activity in a dose dependent manner. Glutamine in low and high dose reserved the improvement of the mean survival time induced by cisplatin. Moreover, pretreatment with glutamine high dose significantly improved the effect of cisplatin on tumor growth delay. These data suggest that glutamine may decrease the toxicity and oxidative stress of cisplatin, besides improving its antitumor efficacy