PT  - JOURNAL ARTICLE
AU  - Matthew R. Durk
AU  - Gauri Deshmukh
AU  - Nicole Valle
AU  - Xiao Ding
AU  - Bianca M Liederer
AU  - Xingrong Liu
TI  - Use of Subcutaneous and Intraperitoneal Administration Methods to Facilitate Cassette Dosing in Microdialysis Studies in Rats
AID  - 10.1124/dmd.118.080697
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.080697
4099  - http://dmd.aspetjournals.org/content/early/2018/04/26/dmd.118.080697.short
4100  - http://dmd.aspetjournals.org/content/early/2018/04/26/dmd.118.080697.full
AB  - Microdialysis is a powerful technique allowing for real-time measurement of unbound drug concentrations in brain interstitial fluid (ISF) in conscious animals. Use of microdialysis in drug discovery is limited by high resource requirement and low throughput, but this may be improved by cassette dosing. Administering multiple compounds intravenously (IV) of diverse physiochemical properties, it is often very challenging and time-consuming to identify a vehicle that can dissolve all the compounds. To overcome this limitation, the present study explores the possibility of administering a cassette dose of 9 diverse compounds (carbamazepine, citalopram, desmethylclozapine, diphenhydramine, gabapentin, metoclopramide, naltrexone, quinidine, and risperidone) in suspension, rather than in solution, by intraperitoneal and subcutaneous routes, and determining if this is a viable option for assessing BBB penetration in microdialysis studies. Repeated hourly subcutaneous dosing during the 6 hour microdialysis study allowed for the best attainment of distributional equilibrium between brain and plasma, resulting in less than two-fold of difference unbound brain to unbound plasma concentration ratio for the cassette dosing method versus the discrete dosing. Both subcutaneous and intraperitoneal repeated dosing can provide a more practical substitute for IV dosing in determining brain penetration of a cassette of diverse compounds in brain microdialysis studies. The results from the present study demonstrate that dosing compounds in suspension represents a practical approach to eliminate the technical challenge and labor-intensive step of preparation of solutions of a mixture of compounds and will enable the use of cassette brain microdialysis method in a CNS drug discovery setting.