title: Angiotensin Converting Enzyme Inhibitors (ACEI) and doxorubicin pharmacokinetics in women receiving adjuvant breast cancer treatment.
abstract: OBJECTIVE
  Doxorubicin (DOX) chemotherapy can cause cardiac complications. Angiotensin converting enzyme inhibitors (ACEI) may protect against these complications. We performed a pharmacokinetics (PK) study to determine whether DOX levels are altered in the presence of ACEI.
  
  
  METHODS
  In this randomized, cross-over, single-blinded drug-drug interaction study, 19 women with breast cancer prescribed DOX and cyclophosphamide every 14 days received one cycle of DOX chemotherapy with ACEI enalapril 10 mg daily and another cycle of DOX with placebo. Blood samples for DOX and doxorubicinol were drawn at baseline, 0.5, 1.0, 2.0, 4.0, 24.0 and 48.0 hours after infusion with and without ACEI enalapril. Correlative laboratories were also obtained. PK data was analyzed using non compartmental methods and DOX and doxorubicinol area under the curve (AUC) 0 to infinity, Cmax and half-life were estimated. Paired t-tests were used to determine whether DOX and its metabolite were altered with the use of enalapril (P < 0.05).
  
  
  RESULTS
  17 women (median age 45 years) received 60 mg/m2 DOX every two weeks for four cycles. Mean (SD) AUC0- ∞ for DOX and doxorubicinol with enalapril exposure was 1185.56 (44.64) hr*ng/ml and 1040 (80.6) hr*ng/ml, respectively. AUC0- ∞ for DOX and doxobubicinol without enalapril was 1167.73 (45.26) hr*ng/ml and 1056.32 (92.03) hr*ng/ml, respectively. There is no interaction between DOX and enalapril. Enalapril was tolerated (33% grade 1 dizziness).
  
  
  CONCLUSIONS
  ACEI, enalapril, does not appear to alter the PK of DOX. Ongoing efforts to determine the effectiveness of ACEI as a cardioprotective agent in women receiving DOX chemotherapy should be continued.
authors: Division of Hematology/Oncology/Transplantation, University of Minnesota, 420 Delaware Street, S.E., MMC 480, Minneapolis, MN 55455 USA.
authors: Anne
authors: A
authors: Blaes
authors: University of Minnesota, Division of Cardiology, Minneapolis, MN USA.
authors: Daniel
authors: D
authors: Duprez
authors: Biostatistics Core, University of Minnesota, Minneapolis, MN USA.
authors: Todd
authors: T
authors: Defor
authors: Biostatistics Core, University of Minnesota, Minneapolis, MN USA.
authors: Ryan
authors: R
authors: Shanley
authors: Division of Hematology/Oncology/Transplantation, University of Minnesota, 420 Delaware Street, S.E., MMC 480, Minneapolis, MN 55455 USA.
authors: Heather
authors: H
authors: Beckwith
authors: Mayo Clinic, Rochester, MN USA.
authors: Tufia
authors: T
authors: Haddad
authors: Division of Hematology/Oncology/Transplantation, University of Minnesota, 420 Delaware Street, S.E., MMC 480, Minneapolis, MN 55455 USA.
authors: David
authors: D
authors: Potter
authors: Division of Hematology/Oncology/Transplantation, University of Minnesota, 420 Delaware Street, S.E., MMC 480, Minneapolis, MN 55455 USA.
authors: Douglas
authors: D
authors: Yee
authors: College of Pharmacy, University of Minnesota, Minneapolis, MN USA.
authors: Kinjal
authors: K
authors: Sanghavi
authors: College of Pharmacy, University of Minnesota, Minneapolis, MN USA.
authors: Pamala
authors: P
authors: Jacobson
keywords: Angiotensin Converting Enzyme Inhibitors; Breast cancer; Cardioprotection; Doxorubicin; Drug interaction; Enalapril; Pharmacokinetics
references: Circulation. 2006 Dec 5;114(23):2474-81
references: 17101852
references: Clin Pharmacol Ther. 1993 May;53(5):555-61
references: 8387903
references: J Clin Oncol. 2009 Oct 1;27(28):4798-808
references: 19687331
references: Clin Pharmacokinet. 2010;49(2):71-87
references: 20067334
references: N Engl J Med. 2011 Oct 6;365(14):1273-83
references: 21991949
references: N Engl J Med. 1999 Feb 25;340(8):654; author reply 655
references: 10049087
references: Clin Pharmacol Ther. 1973 Jul-Aug;14(4):592-600
references: 4723268
references: J Clin Oncol. 1997 Apr;15(4):1318-32
references: 9193323
references: Minn Med. 2010 Oct;93(10):40-4
references: 21140761
references: Pharmacol Res. 2009 Nov;60(5):373-81
references: 19467331
references: Pharmacol Rep. 2008 May-Jun;60(3):382-90
references: 18622063
references: Cancer Invest. 2011 Nov;29(9):585-93
references: 21936625
references: N Engl J Med. 1998 Sep 24;339(13):900-5
references: 9744975
references: J Clin Oncol. 2009 Mar 10;27(8):1177-83
references: 19204201
references: J Clin Oncol. 2012 Oct 20;30(30):3657-64
references: 23008297
references: J Am Coll Cardiol. 2013 Jun 11;61(23):2355-62
references: 23583763
references: Cancer. 2005 Dec 1;104(11):2492-8
references: 16247790
references: J Clin Pharmacol. 2004 Mar;44(3):215-23
references: 14973304
references: J Clin Oncol. 1988 Aug;6(8):1321-7
references: 3411343
references: N Engl J Med. 1999 Feb 25;340(8):654-5
references: 10049088
references: Circulation. 2004 Jun 29;109(25):3122-31
references: 15226229
references: Clin Cancer Res. 2008 Jan 1;14(1):14-24
references: 18172247
references: Am J Hematol. 2010 Nov;85(11):894-6
references: 20872550
references: J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62
references: 17161256
references: Breast Cancer Res Treat. 2011 Sep;129(2):549-56
references: 21479924
references: Cancer Invest. 2010 Mar;28(3):217-9
references: 20128683
references: Expert Rev Anticancer Ther. 2006 Sep;6(9):1249-69
references: 17020459
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jun 1;852(1-2):545-53
references: 17379584
references: J Clin Oncol. 2013 Jun 20;31(18):2265-72
references: 23650417
references: Breast Cancer Res Treat. 2010 Jul;122(2):585-90
references: 20058065