"Interactions Between Taxanes and Breast Cancer Chemotherapy Drugs : Doxorubisin, Cisplatin, and Epirubisin"
Review Interactions Between Taxanes and Breast Cancer Chemotherapy Drugs : Doxorubisin, Cisplatin, and Epirubisin 1 Suhatno, 2Nurkhasanah 1 Pharmacist Program, 2Graduate of Pharmacy Program, Faculty of Pharmacy Ahmad Dahlan University, Yogyakarta, Indonesia Abstrac. Chemotherapy may be given to shrink or control the growth of breast cancer who had metastatic. Inter-drug combination chemotherapy for breast-cancer therapy will further enhance the effect of potential interactions. Interaction can reduce the cytotoxic effects of drugs that will reduce the efficacy of the drug and can cause adverse drugs reaction that would endanger the patient. Writing this article is done by collecting a variety of journals, information from the website on the internet like, Pubmed, government sites, Google Scholar, various books about breast cancer, and breast cancer therapy guidelines. The keyword is used : Taxanes, Drugs Interaction, Breast Cancer in the search field. Results: There was a decrease of doxorubisin elimination when paclitaxel is given in advance of doxorubisin. Provision of cisplatin before taxol increased side effects and neutropenia cardiotoxicity (CHF). Giving paclitaxel before epirubisin can enhance the effects of myelotoxicity. There is no parameter pengeruh farmacokinetics and adverse effects in the order granting the differences between docetaxel and epirubisin. Conclusion: The use of combinations of chemotherapy drugs should be considered as the order of drug administration may influence the pharmacokinetic parameters or side effects of these drugs. Key word: breast cancer, taxane, drug interactions, doxorubisin, cisplatin, epirubisin 1. Introduction Chemotherapy is treatment with anticancer drugs or cytotoxic agents. The purpose of chemotherapy is to destroy breast cancer cells. Chemotherapy is usually given together with surgery and or radiotherapy for primary invasive breast cancer, after surgery and before radiotherapy. Secondary invasive breast cancer or breast cancer that has matastasis is a condition in which breast cancer cells have spread to other body parts such as bones or lungs. Chemotherapy may be given to shrink or control the growth of metastatic breast cancer that has this. The drugs used for chemotherapy include: derivatives Taxanes (paclitaxel and docetaxel), doxorubisin, cyclophosphamide, cisplatin, epirubicin, fluorouracil, methotrexate, capecitabine, vinorelbine and gemcitabine (Brest Canser Care, 2012). Taxanes derivatives, have an important role in the treatment of breast cancer and many of the randomized trial has proven efficacy of both drugs (Sparano et al, 2000). Paclitaxel and docetaxel have emerged in the last two decades as an effective antitumor agent. Paclitaxel is a semi-synthetic taxane that is isolated from the bark of Pacific Yew tree (Taxus brevifolia) that grows in the western United States and Canada (Citroreksoko et al, 1996). Docetaxel is a semi- synthetic taxane from Taxus baccata is an extract. In the market, paclitaxel possessed the trade name Taxol ® and docetaxel has the trade name Taxotere ®. Both of these drugs over the past two decades has been proven as an effective anticancer (Vaishampayan et al, 1999). In Figure 1 the structure of Paclitaxel and docetaxel clams. Figure 1. Chemical structure of docetaxel, a semisynthetic taxane in Taxotere ® and pacitaxel, a natural product of Taxol ® Taxanes second derivative has a similarity in the mechanism of action and activities are included in the broad spektum. It will be many opportunities for the occurrence of interactions. (Vaishampayan et al, 1999). Also in the therapy of breast cancer chemotherapy is often combined with other cytotoxic drugs such as doxorubisin, cisplatin, and epirubisin, combination drug therapy with this drug as an anti-breast cancer will further increase the potential interaction effects. Interaction can reduce the cytotoxic effects of drugs that will reduce the efficacy of the drug. Besides the interaction may lead to adverse drugs reaction that would endanger the patient. 2. Method . 3. Result Based on the obtained several scientific journals, then reassembled and displayed by means of narrative in the following table : Title, Author names, No Sampel Result year 1. Sequence-dependent 8 breast cancer Due to the reduced alteration of patients elimination of doxorubisin doxorubicin when paclitaxel is given in pharmacokinetics by advance of doxorubisin paclitaxel and doxorubicin in patients with metastatic breast cancer. Holmes et al. (1996). 2. Sequences of taxol and breast cancer Provision of cisplatin before cisplatin :a phase I and patients taxol increased side effects pharmacologic study. and neutropenia cardiotosiknya (CHF) Rowanski et al. (1991) 3. Squences effect of 21 breast Giving paclitaxel before epirubicin and cancer patients epirubisin enhance the paclitaxel treatment on effects of myelotoxicity pharmacokinetics and toxicity. Venturi et al. (2001) 4 Influence of alternate 12 breast There was no effect of the sequences of epirubicin cancer patients pharmacokinetic parameters and docetaxel on the and side effects in the order pharmacokinetic granting the differences behavior of both drugs in advanced breast between docetaxel and cancer. epirubisin Lunardi et al. (2001) . 4. Discuss 4.1. Paclitaxel and Doxorubisin The combination of doxorubisin (DOX) and paclitaxel (PTX) has demonstrated increased efficacy of the treatment of various cancers, especially breast cancer. Combination of both drugs cause interactions based on the sequence and timing of administration. In this case, when administered prior to DOX PTX increased incidence of severe mucositis and neutropenia. In the PTX before DOX administration was also followed by increased levels of DOX, DOX metabolite of alcohol (doxorubicinol I). Increased levels of DOX in several studies been shown to increase the incidence of cardiotoxic. In the research conducted by Gianni et al. (1995) on the dose and sequence of drug administration, involving 35 patients, PTX is administered as a 3-hour infusion in combination with DOX. PTX infusion is given first and 15 minutes after the infusion of new low PTX administered at a dose of DOX (60mg/m2). The results showed a higher incidence of CHF than expected (5 patients experienced CHF) than DOX administration alone. But there was no difference in side effects include neutropenia, mucosistis, peripheral neuropathy and myalgia / arthralgia. Holmes et al. (1996) reported that changes in the pharmacokinetics of DOX by PTX depends on the sequence of drug administration. In that study, PTX administered intravenously during the first 24 hours. After being awarded doxorubisin infusion for 48 hours. This results in 32% decrease in plasma Clearence and concentrations (Cmax) 70% higher. Thus, doxorubisin should be given in advance of paclitaxel 4.2. Paclitaxel and Cisplatin Research conducted by Rowinsky et al (1991), the occurrence of drug interactions based on the order of administration also occurred in cisplatin and paclitaxel. Infusion of cisplatin at a dose of 75mg/m2 and 1mg/menit speed, followed by paclitaxel at a dose of 135mg/m2 infusa for 24 hours, there was a side effect of neutropenia. In pharmacology, showed differences in elimination of taxol decreased by 25% when cisplatin is given first of taxol. Reduction mechanism by cisplatin paclitaxel elimination process is not known with certainty. Paclitaxel alone merupakakan drugs that are metabolized in the liver by an enzyme system sitrokrom P450 (Vaishampayan et al, 1999). Research conducted Leblanc et al (1992) revealed that administration of cisplatin followed by paclitaxel in mice, decreased elimination of paclitaxel. This decline occurred because the elimination of cisplatin induces modulation of cytochrome P450 enzyme system in the elimination of paclitaxel. 4.3. Paclitaxel and Docetaxel interaction with epirubisin Pharmacokinetic interaction between epirubisin and paclitaxel in 20 breast cancer patients studied by Esposito et al (1999). Paclitaxel and docetaxel significantly merupabah metabolic profiles of epirubisin. Epirubisin given with paclitaxel and docetaxel had a higher AUC compared with patients given epirubisin only. 7-deoxydoxorubicinone, metabolites of epirubisin products also undergo significant changes are characterized by a higher AUC. Treatment with paclitaxel also showed an increase of epirubisin glukoronidase. It tersebuh effect on increasing the elimination of active drug substance in the blood circulation. Pharmacokinetic interactions in the order granting epirubisin after paclitaxel in breast cancer patients studied by Venturi et al (2000). The study was conducted by giving epirubisin intravenously and followed by intravenous infusion of paclitaxel for 3 h or with the opposite order. In the first administration of paclitaxel, a significant increase in toxic effects hematologic and 36% increase in AUC of epirubisin. Tosik hematologic effects occurring is increased myelotoxitcity. To avoid an increase in toxic effects when combined epirubisin epirubisin and paclitaxel should be given in advance of paclitaxel. It can also be done by providing 24-hour interval after the first drug administration. Lunardi et al (2002) conducted a study on the influence of the order granting the epirubisin and docetaxel on the pharmacokinetic profile in patients with breast cancer. The samples used were 12 patients with breast cancer by administering epirubisin intravenously followed by intravenous docetaxel administration for an hour or vice versa. The results showed no change in the pharmacokinetic parameters epirubisin. This suggests that the sequence of drug administration had no effect on the metabolism epirubisin. Moreover there is no change in hematological toxic effects and non-hematologic. 5. Conclusion On the use of combinations of chemotherapy drugs should be considered as the order of drug administration may influence the pharmacokinetic parameters or side effects of these drugs. 6. Acknowledgments Dr. Nurkhasanah, M.Sc., Apt as the mentors who have guided and provide steering for the preparation of review articles. References 1. Breast Cancer Care. 2012. Chemotherapy for breast cancer, http:// www.breastcancercare.org.uk/sites/default/files/bcc16_chemotherapy_201 2_1.pdf (May 26, 2012) 2. Citroreksoko, P. 1996. Warta Biotek Tahun X No.4. 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