Related Articles Effect of para halogen modification of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides on metabolism and clearance.Arch Pharm Res. 2013 Oct 9;
Authors: Kim J, Coss CC, Dalton JT
Abstract
The purpose of this~ study was to better understand why 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 protect benzene ring from hydroxylation. We determined the plasma protein binding of this series of halogen substituted SARMs and characterized the qualitative effects of B-ring halogen substitution on in vivo metabolism. In vivo metabolism of S-9, S-10, and S-11 were determined in rats using LC-MS(n) analysis. Intrinsic clearance was measured by in vitro metabolism using rat liver microsomes. Rat plasma protein binding was measured by equilibrium dialysis and drug concentrations after dialysis were analyzed by LC-MS. The major metabolic pathways of the halogen-substituted SARMs examined were very 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 plasma protein binding studies, S-1 (F, fu~=~0.78~±~0.17~%) showed the 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~?L/min/mg, respectively. These findings suggest that as lipophilicity increased the free fraction was reduced thus compensating for metabolic liability and resulting in the apparent discrepancy between CLint and CL total of halogen-substituted SARMs series.
PMID: 24105418 [PubMed - as supplied by publisher]
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