title: Lapatinib promotes the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes.
abstract: Lapatinib has been used in combination with capecitabine or paclitaxel to treat patients with progressive HER2-overexpressing metastatic breast cancer (MBC). Unfortunately, an increased incidence of hepatotoxicity had been reported in the combinational therapy. The aim of this study was to investigate the potential mechanisms of this combinational therapy. We found that the patients receiving lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those receiving paclitaxel alone. Lapatinib was shown to increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1. Pharmacokinetic studies revealed that lapatinib could increase the systematic exposure of paclitaxel and doxorubicin. Moreover, the in vivo experiments showed that the levels of alanine aminotransferase and serious hepatocyte injury in the group of lapatinib plus chemotherapeutic agent were significantly higher than those in the group of single chemotherapeutic agent such as paclitaxel or doxorubicin. Our study thus revealed for the first time that the higher incidence of hepatotoxicity during this combinational treatment was due to the increased drug accumulation in hepatocytes mediated by the inhibition of ABCB1 by lapatinib. Appropriate dose adjustment may be needed to optimize the combination therapy.
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: ChunLing
authors.initials: C
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: ShaoLin
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: HongYun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: XingPing
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: ZhenCong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
authors.forename: ZheSheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Kenneth
authors.initials: K
authors.lastname: To
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: LiWu
authors.initials: L
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D000077341:Lapatinib; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D011799:Quinazolines; D000077341:Lapatinib; D004317:Doxorubicin; D017239:Paclitaxel
keywords: ABC transporters; hepatotoxicity; lapatinib; pharmacokinetic