Effect of structural alterations on the biotransformation rate of glucocorticosteroids in rat and human liver.
The effect of structural alterations on the biotransformation rate of glucocorticosteroids (GCS) by rat- and human-liver 9000 g supernatant fraction was studied. Insertion of a 16 alpha-hydroxy group in the prednisolone molecule (16 alpha-hydroxyprednisolone) was found to decrease the rate of biotransformation. Substitution of the 16 alpha,17 alpha-hydroxy groups with a symmetric acetal (in, for example, desonide) or especially a non-symmetric acetal (in, for example, budesonide), enhanced the biotransformation rate several-fold, particularly in human liver. Differences in the rates of metabolism in rat and human liver were observed. Hydrogenation of the 1,2-double bond in prednisolone and budesonide (hydrocortisone and 1,2-dihydrobudesonide) enhanced the biotransformation rate nine-fold in rat liver but only two-fold in human liver. Fluorination of the steroid nucleus in 6 alpha- and 9 alpha-positions enhanced the biotransformation rate several-fold in human liver, but in rat liver fluorination marginally decreased the rate of biotransformation. These in vitro results correlate well with available data on the first-pass liver metabolism of the studied GCS. This indicates that in vitro data can be useful in predicting oral bioavailability of GCS.
D000818:Animals; D001711:Biotransformation; D019819:Budesonide; D003898:Desonide / Q000378:metabolism; D005446:Fluocinolone Acetonide / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D011239:Prednisolone / Q000494:pharmacology; D011282:Pregnenediones / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014222:Triamcinolone Acetonide / Q000378:metabolism
D005938:Glucocorticoids; D011282:Pregnenediones; D005446:Fluocinolone Acetonide; D019819:Budesonide; D011239:Prednisolone; D014222:Triamcinolone Acetonide; D003898:Desonide