RT Journal Article
SR Electronic
T1 Use of the Cassette-Dosing Approach to Assess Brain Penetration in Drug Discovery
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 963
OP 969
DO 10.1124/dmd.111.044420
VO 40
IS 5
A1 Xingrong Liu
A1 Xiao Ding
A1 Gauri Deshmukh
A1 Bianca M. Liederer
A1 Cornelis E. C. A. Hop
YR 2012
UL http://dmd.aspetjournals.org/content/40/5/963.abstract
AB 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, Kp). 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 Kp determined from discrete dosing in wild-type mice and their Kp 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 Kp 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 Kp values estimated by mass spectrometry responses, namely the ratio of compound peak area to internal standard peak area, were within 2-fold of the Kp observed from the actual concentrations. Furthermore, the ratios of Kp in Mdr1a/1b(−/−), Bcrp1(−/−), and Mdr1a/1b(−/−)/Bcrp1(−/−) mice versus the Kp in the wild-type mice from cassette dosing were consistent with the ones reported in the literature where the compounds were dosed discretely. These results demonstrate that drug-drug interactions at the blood-brain barrier are unlikely at a subcutaneous dose of 1 to 3 mg/kg and support the use of the cassette dosing approach to assess brain penetration in drug discovery.