Pharmacokinetic interaction of entinostat and lapatinib following single and co-oral administration in rats.
1. Entinostat, also known as SNDX-275 or MS-275, is a novel, potent, orally bioavailable, class I selective histone deacetylase inhibitor. Pre-clinical data has show that MS-275 can enhance the activity of lapatinib in HER(2+) metastatic inflammatory and non-inflammatory breast cancer. This study examined whether oral administration of MS-275 to the rats with lapatinib led to any pharmacokinetic interactions. 2. To evaluate pharmacokinetic interaction of MS-275 and lapatinib in rat, a sensitive and simple LC-MS method was developed to simultaneously determine MS-275 and lapatinib in rat plasma with carbamazepine as internal standard (IS). Eighteen rats were divided randomly into three groups, lapatinib group (lapatinib 15 mg/kg, n = 8), MS-275 group (MS-275 15 mg/kg, n = 8) and co-administration group (MS-275 15 mg/kg and lapatinib 15 mg/kg, n = 8). 3. There was no statistical pharmacokinetics difference for MS-275 in MS-275 group and co-administration group; the lapatinib could not influence the pharmacokinetic profile of MS-275 in rats. However, there is a statistical pharmacokinetics difference between lapatinib in the lapatinib group and co-administration group, when co-oral administration MS-275 with lapatinib, AUC increased from 2375.5 to 9900.3 ng/mL h (p < 0.05), Cmax increased from 538.0 to 2578.2 ng/mL (p < 0.01), CL decreased from 6.2 to 1.7 L/h/kg (p < 0.01). 4. These data indicate MS-275 could obviously influence the pharmacokinetic profile of lapatinib in rats, which might cause drug-drug interactions in humans when using lapatinib with MS-275. Further investigations should be carried out to elucidate the synergistic mechanisms between the two drugs.
Department of Clinical Pharmacy, the First Affiliated Hospital of Wenzhou Medical University , Wenzhou , China and.
Xuezhi
X
Yang
Qingwei
Q
Zhang
Mengchun
M
Chen
Lufeng
L
Hu
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001549:Benzamides / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004347:Drug Interactions; D000077341:Lapatinib; D008297:Male; D013058:Mass Spectrometry; D011725:Pyridines / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D001549:Benzamides; D011725:Pyridines; D011799:Quinazolines; D000077341:Lapatinib; C118739:entinostat
Entinostat; interaction; lapatinib; pharmacokinetic; rat