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- 저자 : James T. Dalton (검색결과 1 건)
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김주현,Christopher C. Coss,James T. Dalton 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.11
The purpose of this study was to better understandwhy para-halogen modifications of S-3-(4-halophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide selective androgen receptor modulators(SARMs) had the opposite of expected effects on total clearance,in which electron-withdrawing groups generally protectbenzene ring from hydroxylation. We determined the plasmaprotein binding of this series of halogen substituted SARMsand characterized the qualitative effects of B-ring halogensubstitution on in vivometabolism. In vivometabolismof S-9,S-10, and S-11 were determined in rats using LC-MSn analysis. Intrinsic clearance was measured by in vitro metabolismusing rat liver microsomes. Rat plasma protein binding wasmeasured by equilibrium dialysis and drug concentrationsafter dialysis were analyzed by LC-MS. The major metabolicpathways of the halogen-substituted SARMs examined werevery similar and included three major phase I pathways; (1)hydrolysis of the amide bond, (2) B-ring hydroxylation, and(3) A-ring nitro reduction to an aromatic amine. In plasmaprotein binding studies, S-1 (F, fu = 0.78 ± 0.17 %) showedthe greatest unbound fraction, followed by S-9 (Cl, fu =0.10 ± 0.04 %), S-10 (Br, fu = 0.03 ± 0.01 %), and S-11 (I,fu = 0.008 ± 0.001 %). The CLint values of S-1, S-9, S-10,and S-11 were 2.4, 2.5, 2.8, and 4.6 lL/min/mg, respectively. These findings suggest that as lipophilicity increased the freefraction was reduced thus compensating for metabolic liabilityand resulting in the apparent discrepancy between CLintand CL total of halogen-substituted SARMs series.
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