In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Abstract

ABSTRACT:Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(؊/؊) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(؊/؊) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(؊/؊) mice were 1.3-to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(؊/؊) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.

The Role of the Breast Cancer Resistance Protein (ABCG2) in the Distribution of Sorafenib to the Brain

“…The steady-state brain-to-plasma ratio in the wild-type mice was not statistically different from the ratio in the Mdr1a/b(Ϫ/Ϫ) mice (0.11 Ϯ 0.021). This finding is similar to those by Lagas et al (2010) and Gnoth et al (2010), who also report a lack of P-gp mediated transport in vivo. (Fig.…”

“…This is especially relevant to an infiltrative disease such as glioma, where invasive tumor cells that may reside behind an intact BBB might be deprived of a drug that is effluxed by P-gp and BCRP. Several studies have attempted to explain the interaction of sorafenib with P-gp and BCRP, two critical efflux transporters at the BBB (Hu et al, 2009;Gnoth et al, 2010;Lagas et al, 2010). However, those studies failed to reach a consensus with respect to the role of the two proteins in limiting the CNS penetration of sorafenib.…”

“…In contrast, Lagas et al (2010) reported that sorafenib is a substrate for both P-gp and BCRP that limit its brain accumulation. Furthermore, another study (Gnoth et al, 2010) reported that P-gp does not affect plasma sorafenib exposure and might not limit transport of sorafenib across the BBB. Therefore, the interaction of sorafenib with transporters in the BBB is not fully elucidated.…”

Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

“…Therefore, its bioavailability is influenced by the activity of the excretory transporters ABCB1 and ABCG2 in the small-intestinal mucosa (Hu et al 2009;Gnoth et al 2010). In addition, sorafenib is primarily metabolized by cytochrome P450 3A4 (CYP3A4) in the small-intestinal mucosa or the liver, and it is also subjected to glucuronidation mediated by uridine diphosphate glucuronosyl transferase (UGT) 1A9 (Lathia et al 2006;Peer et al 2012;Filppula et al 2014).…”

Sorafenib Hepatobiliary Disposition: Mechanisms of Hepatic Uptake and Disposition of Generated Metabolites

“…Transporters located in the apical membrane involved in the removal of drug and metabolite(s) into the bile canaliculus include P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP2), breast cancer resistance protein (BCRP), and the bile salt export pump. Sorafenib is a weak substrate for P-gp, but the overall effect of this transporter on plasma concentrations is low based on in vivo results using mdr1a/1b(-/-) knockout mice (Gnoth et al, 2010).…”