The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid

• Published in: Investigational new drugs Vol. 38; no. 3; pp. 574 - 583
• Main Authors: Karbownik, Agnieszka, Sobańska, Katarzyna, Płotek, Włodzimierz, Grabowski, Tomasz, Klupczynska, Agnieszka, Plewa, Szymon, Grześkowiak, Edmund, Szałek, Edyta
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2020; Springer Nature B.V
• Subjects: Blood plasma; Blood-brain barrier; Breast cancer; Cerebrospinal fluid; Enzyme inhibitors; Epidermal growth factor receptors; ErbB-2 protein; Glycoproteins; Inhibitor drugs; Inhibitors; Kinases; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Medicine; Medicine & Public Health; Metastases; Oncology; P-Glycoprotein; Penetration; Penetration resistance; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Preclinical Studies; Protein transport; Protein-tyrosine kinase; Proteins; Studies; Targeted cancer therapy; Tyrosine; Elacridar; Lapatinib; Blood-cerebrospinal fluid barrier; Blood-brain barrier
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-019-00806-3

Summary Background Lapatinib is a small-molecule tyrosine kinase inhibitor of human epidermal receptor 2 (HER2) and EGFR that has currently been approved for the treatment of HER2-positive advanced and metastatic breast cancer (BC). The ATP-binding cassette (ABC) family of transporters includes P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2), which substantially restrict the penetration of drugs, including chemotherapeutics, through the blood-brain barrier and blood-cerebrospinal fluid barrier. The aim of this study was to investigate the effects of elacridar, an ABCB1 and ABCG2 inhibitor, on the brain and cerebrospinal fluid uptake of lapatinib. Methods Rats were divided into two groups: one group received 5 mg/kg elacridar and 100 mg/kg lapatinib (an experimental group), and the other group received 100 mg/kg lapatinib (a control group). Lapatinib concentrations in the blood plasma (BP), cerebrospinal fluid (CSF) and brain tissue (BT) were measured by liquid chromatography coupled with tandem mass spectrometry. Results Elacridar significantly increased lapatinib penetration into the CSF and BT (C max increase of 136.4% and 54.7% and AUC 0-∞ increase of 53.7% and 86.5%, respectively). The C max of lapatinib in BP was similar in both experimental groups (3057.5 vs. 3257.5 ng/mL, respectively). Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases.