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Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species

	author = {Chen-chun ZHONG and Feng CHEN and Jun-ling YANG and Wei-wei JIA and Li LI and Chen CHENG and Fei-fei DU and Su-ping ZHANG and Chengying XIE and Na-ting ZHANG and Olajide E OLALEYE and Feng-qing WANG and Fang XU and Li-guang LOU and Dong-ying CHEN and Wei NIU and Chuan LI},
	title = {Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species},
	journal = {Acta Pharmacologica Sinica},
	volume = {39},
	number = {6},
	year = {2018},
	keywords = {},
	abstract = {Abstract
Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%–58% in rats and 41%–77% in dogs. Terminal half-life of anlotinib in dogs (22.8±11.0 h) was longer than that in rats (5.1±1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L·h–1·kg–1; dogs, 0.40±0.06 L·h–1·kg–1). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6±3.1 L/kg) and dogs (6.6±2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to α1-acid glycoprotein or γ-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, },
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