Use of the cassette-dosing approach to assess brain penetration in drug discovery

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Xingrong LiuCornelis E C A Hop

Abstract

The objective of the present study was to examine the cassette dosing method in determination of brain-to-plasma concentration ratio (area under the concentration-time profiles for plasma/area under the concentration-time profiles for brain, K(p)). Eleven model compounds, amprenavir, citalopram, digoxin, elacridar, imatinib, (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester (Ko143), loperamide, prazosin, quinidine, sulfasalazine, and verapamil, were selected to compare their K(p) determined from discrete dosing in wild-type mice and their K(p) from cassette dosing in wild-type, Mdr1a/1b(-/-), Bcrp1(-/-), and Mdr1a/1b(-/-)/Bcrp1(-/-) mice at 1 to 3 mg/kg. The mice brain and plasma were collected at 0.25, 1, and 3 h and were analyzed using high-performance liquid chromatography-tandem mass spectrometry methods. The K(p) determined from discrete dosing versus cassette dosing in the wild-type mice were within 2-fold for all the compounds except sulfasalazine and Ko143. The brain concentrations of sulfasalazine and Ko143 and the plasma concentrations of Ko143 were below the lower limit of quantitation. In addition, the K(p) ...Continue Reading

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Citations

Jul 5, 2013·Bioanalysis·Xianmei CaiWilson Z Shou
Nov 12, 2015·Journal of Pharmaceutical Sciences·Atsushi KitamuraYoshiharu Deguchi
Feb 12, 2015·Clinical Pharmacology and Therapeutics·E C M de Lange, M Hammarlund-Udenaes
Jan 27, 2015·Progress in Neuro-psychopharmacology & Biological Psychiatry·Eduard BenteaIlse Smolders
May 18, 2016·The Journal of Pharmacology and Experimental Therapeutics·John OberdickWolfgang Sadee
Feb 2, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Minjee KimWilliam F Elmquist
May 7, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Gauri DeshmukhXingrong Liu
Jul 8, 2015·The Journal of Pharmacology and Experimental Therapeutics·Lora D WeidnerMatthew D Hall
Dec 3, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Keumhan NohCong Wei

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