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The Influence of Paracetamol on the Penetration of Sorafenib and Sorafenib N-Oxide Through the Blood-Brain Barrier in Rats.

Abstract：

BACKGROUND AND OBJECTIVE:Sorafenib is an oral, multikinase inhibitor with established single-agent activity in several tumor types. Sorafenib was moderately transported by P-glycoprotein (P-gp) and more efficiently by breast cancer resistance protein. The constitutive androstane receptor (CAR) is a ligand-activated transcription factor involved in P-gp regulation in the brain microvasculature. Paracetamol is a CAR activator. The purpose of this study was to investigate the effect of paracetamol on the brain uptake of sorafenib and sorafenib N-oxide. METHODS:The rats were assigned to two groups-rats receiving oral paracetamol 100 mg/kg and sorafenib 100 mg/kg (n = 42, ISR+PA) and rats receiving oral vehicle and sorafenib 100 mg/kg (n = 42, IISR). The sorafenib and sorafenib N-oxide concentrations in blood plasma and brain tissue were determined by a high-performance liquid chromatography method with ultraviolet detection. Brain-to-plasma partition coefficient (Kp) was calculated as a ratio of the area under the curve from zero to 24 h (AUC) in the brain and plasma. A drug targeting index (DTI) was estimated as the group ISR+PA Kp to group IISR Kp ratio. RESULTS:Pharmacokinetic analysis revealed increased brain exposure to sorafenib and sorafenib N-oxide after co-administration of paracetamol. The brain maximum concentration (Cmax) and the AUC of the parent drug in the ISR+PA group compared with the IISR group were greater by 49.5 and 77.8%, respectively, and the same parameters for the metabolite were higher by 51.4 and 50.9%. However, the Kp values of sorafenib and sorafenib N-oxide did not differ significantly between the two animal groups and the DTI values were close to 1. CONCLUSION:Paracetamol increases exposure to sorafenib and sorafenib N-oxide in the brain, likely due to increased exposure in plasma.

journal_name

Eur J Drug Metab Pharmacokinet

journal_title

European journal of drug metabolism and pharmacokinetics

authors

Karbownik A,Stanisławiak-Rudowicz J,Stachowiak A,Romański M,Grześkowiak E,Szałek E

doi

10.1007/s13318-020-00639-z

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

801-808

issue

eissn

0378-7966

issn

2107-0180

pii

10.1007/s13318-020-00639-z

journal_volume

pub_type

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The Influence of Paracetamol on the Penetration of Sorafenib and Sorafenib N-Oxide Through the Blood-Brain Barrier in Rats.