Interactions Between Taxanes and Breast Cancer Chemotherapy Drugs : Doxorubisin, Cisplatin, and Epirubisin by sumokaryono


More Info
Interactions Between Taxanes and Breast Cancer Chemotherapy
         Drugs : Doxorubisin, Cisplatin, and Epirubisin
                                   Suhatno, 2Nurkhasanah
       Pharmacist Program, 2Graduate of Pharmacy Program, Faculty of Pharmacy
                   Ahmad Dahlan University, Yogyakarta, Indonesia

         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,


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,
   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
 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
              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
              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
                                                         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.


   1. Breast Cancer Care. 2012. Chemotherapy for breast cancer,
      2_1.pdf (May 26, 2012)
   2. Citroreksoko, P. 1996. Warta Biotek Tahun X No.4. Bogor : LIPI
   3. Esposito M, VenturiniM, Vannozzi MO et al.1999. ”Comparative effects
      of paclitaxel and docetaxel on the metabolism and pharmacokinetics of
      epirubicin in breast cancer patients”. J Clin Oncol : 1132-1140
   4. Gianni L, Munzone E, Capri et al.1995. ”Paclitaxel by 3-hour infusion in
      combination with bolus doxorubicin in women with untreated breast
      cancer : high antitumor efficacy and cardiac effects in a dose-finding and
      sequence-finding study”. J clin Oncol : 2688-2699
   5. Holmes FA, Madden T, Newman RA, et al. 1996. “Sequence-dependent
      alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I
      study of paclitaxel and doxorubicin in patients with metastatic breast
      cancer”. J Clin Oncol : 2713-2721
   6. LeBlanc GA, Sundseth SS, Weber GF, Waxman DJ. 1992. “Platinum
      anticancer drugs modulate P-450 mRNA levels and differentially alter
      hepatic drug and steroid hormone metabolism in male and female rats”.
      Cancer Res : 540-547
   7. Lunardi G, Venturini M, Vannozzi MO, Toline G. et al. 2002. “Influence
      of alternate sequences of epirubicin and docetaxel on the pharmacokinetics
      behavior of both durgs in advanced breast cancer”. Annals of Oncology :
8. Rowinsky EK, Gilbert MR, McGuire WP et al. 1991. “Sequences of taxol
    and cisplatin : a phase I and pharmacologic study”. J Clin Oncol : 1692-
9. Sparano JA, Speyer J, Gradishar WJ. 1999. “Phase I trial of escalating
    doses of paclitaxel plus doxorubicin and dexrazoxane in patients with
    advanced breast cancer”. J Clin Oncol : 880-886
10. Vaishampayan U, Parchment R, Jasti B, Hussain M. 1999. “ Taxanes : an
    overview of pharmacokinetics. Urology : 22-29
11. Venturini M, Lunardi G, Del Mastro L et al. 2000. “Sequence effect of
    epirubicin and paclitaxel treatment on pharmacokinetics and toxicity”. J
    clin Onc : 2116-2125

To top