title: Evaluation of the pharmacokinetics and cardiotoxicity of doxorubicin in rat receiving nilotinib.
abstract: Doxorubicin (DOX) is a potent chemotherapy drug with a narrow therapeutic window. Nilotinib, a small-molecule Bcr-Abl tyrosine kinase inhibitor, was reported to reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) transmembrane transporters. The present study aimed to investigate nilotinib's affection on the steady-state pharmacokinetics, disposition and cardiotoxicity of DOX. A total of 24 male Sprague-Dawley rats were randomized into four groups (6 in each) and received the following regimens: saline, intravenous DOX (5mg/kg) alone, and DOX co-administrated with either 20 or 40mg/kg nilotinib. Blood was withdrawn at 12 time points till 72h after DOX injection and the concentrations of DOX and its metabolite doxorubicinol (DOXol) in serum and cardiac tissue were assayed by LC-MS-MS method. To determine the cardiotoxicity, the following parameters were investigated: creatine kinase, lactate dehydrogenase, malondialdehyde, and superoxide dismutase. Histopathological examination of heart section was carried out to evaluate the extent of cardiotoxicity after treatments. The results showed that pretreatment of 40mg/kg nilotinib increased the AUC0-t and Cmax of DOX and DOXol. However, their accumulation in cardiac tissue was significantly decreased when compared with the group that received DOX alone. In addition, biochemical and histopathological results showed that 40mg/kg nilotinib reduced the cardiotoxicity induced by DOX administration. In conclusion, co-administration of nilotinib increased serum exposure, but significantly decreased the accumulation of DOX in cardiac tissue. Consistent with in vitro profile, oral dose of 40mg/kg nilotinib significantly decreased the cardiotoxicity of DOX in rat by enhancing P-gp activity in the heart.
authors.affiliation: Department of Pharmacy, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, 200233 Shanghai, China; School of Pharmacy, Shanghai Jiao Tong University, 200240 Shanghai, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Zhou
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Wan
authors.forename: Quan-Jun
authors.initials: QJ
authors.lastname: Yang
authors.forename: Yong-Long
authors.initials: YL
authors.lastname: Han
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.forename: Cheng
authors.initials: C
authors.lastname: Guo
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity*; D019540:Area Under Curve; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D004317:Doxorubicin; D011505:Protein-Tyrosine Kinases; C498826:nilotinib
keywords: Cardiotoxicity; Disposition; Doxorubicin; Nilotinib; P-Glycoprotein; Pharmacokinetic