title: Application of a sample pooling method for the accelerated assessment of the rate of uptake of drugs by the brain in rats.
abstract: The purpose of this study was to examine the feasibility of applying a sample pooling method to the accelerated estimation of the uptake clearance of drugs to the brain in rats. Brain uptake clearances (CL(uptake)) were estimated for five model compounds using the sample pooling method and an integration plot analysis. CL(uptake) was also evaluated for caffeine and theophylline by brain microdialysis. The parameters and throughput of the pooling method were compared with those of typically used standard methods. The correlation for CL(uptake) was statistically significant (P<0.005) between the integration plot and the current method; the throughput of evaluation was 15-fold higher for the sample pooling method. A comparison of CL(uptake) values indicated that the three methods showed comparable results for caffeine while the CL(uptake) of theophylline using the proposed method was significantly different from those of the other methods. A kinetic analysis indicated that a compound with a slower CL(uptake) and longer half-life (e.g., theophylline) is more prone to error and that the lower limit of the CL(uptake) of 0.17 mL min(-1) (g brain)(-1) may be set so as to have an error less than 20% of the estimation. These results suggest that the sample pooling method is applicable for use in the accelerated estimation of the uptake clearance of compounds in the brain for which the value is greater than 0.17 mL min(-1) (g brain)(-1).
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Kang-Pil
authors.initials: KP
authors.lastname: Kim
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Jong-Hyuk
authors.initials: JH
authors.lastname: Sung
authors.forename: Tae-Sung
authors.initials: TS
authors.lastname: Koo
authors.forename: Myong-Joo
authors.initials: MJ
authors.lastname: Byun
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002110:Caffeine / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000493:pharmacokinetics
chemical_list: D002110:Caffeine; D013806:Theophylline