ABSTRACT
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
Subject(s)
Animals, Laboratory , Antineoplastic Agents, Phytogenic , ATP Binding Cassette Transporter, Subfamily B, Member 1 , MiceABSTRACT
Doxorubicin [DOX] is an anthracycline antibiotic with broad-spectrum antitumor activity. Its effectiveness has been limited by the occurrence of dose related myocardial and bone marrow toxicity. L-carnitine is tested in this study to evaluate its protective effect against DOX induced cytotoxicity and genotoxicity. Four groups of adult female rats, each of 15 animals were used; one is used as control receiving 0.5 ml of saline, the other groups received either DOX [3mg/kg], L-carnitine [100mg/kg] or a combination of the two drugs. The treatment was continued i.p. every other day for two weeks. Five animals of each group were injected with 0.2ml of colchicine 2 h before sacrifice, which took place 24 h after the last treatment. Cardiotoxicity was assessed by measuring the serum levels of lactic acid dehydrogenase [LDH], creatine phosphokinase [CPK], glutamic oxaloacetic transaminase [GOT]. Reduced glutathione [GSH], malonaldehyde [MDA] and mitochondrial palmitoyl Co-A and octanoate oxidation were also, determined in cardiac tissue homogenate. The femurs were removed and bone marrow was processed for the preparation of metaphase chromosomes and determination of mitotic activity. DOX significantly increased LDH, CPK, GOT and MDA and significantly decreased GSH and palmitoyl Co-A. Administration of L-carnitine one hour before DOX treatment caused significant recovery for the serum enzymes LDH, CPK, GOT, and MDA, GSH and palmitoyl Co-A. Cytogenetic analysis showed that DOX increased the incidence of chromosomal aberration 18.4% in bone marrow cells and inhibited mitosis to about 50% of its normal rate. Administration of L-carnitine one hour before treatment with DOX significantly decreased the incidence of chromosomal aberrations [14.8%] and increased mitotic activity [10.4]. The results suggest that the cardiotoxicity and genotoxicity induced by DOX took place via a number of possible mechanisms. The results obtained suggest that L-carnitine could be used together with DOX as an adjuvant therapy