Chirality effect of C-20 on metabolism of methyl 11beta,17alpha,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate derivatives.

Epimers at C-20 of methyl 11beta,17alpha,20-trihydroxy-3-oxo-1,4-pregnadien-21-oates, their 9alpha-fluoro analogs, their carbonate derivatives, and their acetonide derivatives were subjected to metabolism study in rat plasma and rat liver homogenate. These steroids were synthesized based on the antedrug concept. In rat plasma, the carboxy ester bonds of 20beta-triols and their acetonides were hydrolyzed with half-lives (T(1/2)) of between 5.7 and 7.7 min, while their corresponding alpha-epimers had longer half-lives of more than 2.5 h. A more profound difference was observed between the alpha- and beta-epimers of the carbonates, with the latter showing a T(1/2) less than 1 min (0.3 and 0.43 min for P20beta- and PF20beta-carbonate, respectively), while that of the former about 3 h (165 min for P20alpha-carbonate and 191 min for PF20alpha-carbonate). In rat liver homogenate, the triol and acetonide derivatives showed greater stability than they did in rat plasma, with T(1/2) for the beta-group in the range of 54-108 min, and T(1/2) for the alpha-group over 7 h. A significant difference in hydrolysis of the carbonate derivatives was also observed in rat liver homogenate. The half-lives of P20beta- and PF20beta-carbonate were 0.67 and 0.66 min, respectively, and the alpha-isomers showed the similar metabolic rate with other alpha-isomers. An esterase inhibitor effectively blocked the hydrolysis of the ester bond, indicating that this metabolism is an enzymatic reaction. Molecular modeling studies show that steric hindrance around the ester group of the alpha-epimers is much greater than that of their beta-counterparts, affording one explanation for the large difference in the metabolic hydrolysis rate; i.e. the carboxy ester bond of beta-isomer which is less hindered sterically than their counter alpha-isomers is hydrolyzed faster than that of alpha-isomers. In conclusion, this study confirms that chirality at C-20 had profound effects on metabolism and pharmacological profile of the steroid acid ester derivatives.