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Abstract
1. The effect of structural alterations on the biotransformation rate of glucocorticosteroids (GCS) by rat- and human-liver 9000g supernatant fraction was studied.
2. Insertion of a 16α-hydroxy group in the prednisolone molecule (16α-hydroxyprednisolone) was found to decrease the rate of biotransformation. Substitution of the 16α,l7α-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.
3. 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 6α- and 9α-positions enhanced the biotransformation rate several-fold in human liver, but in rat liver fluorination marginally decreased the rate of biotransformation.
4. 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.