Pharmacokinetics and ‘bioactivation’ of MPA

In order to display its pharmacological and therapeutic effects, a local corticosteroid has to be bioavailable at its target site in the skin. The intensity and duration of its activity depend on the time course of its concentration in the target tissue, the number of receptors within this, tissue and on the intrinsic pharmacological activity of the molecule respectively of its active metabolite(s). It is commonly accepted that the desired and the adverse corticosteroid effects are mediated by receptor mechanisms. Since all nucleated cells contain corticosteroid receptors with the same specifity yet in different numbers, a dissociation between wanted anti‐inflammatory and unwanted local and systemic effects is not achievable at the receptor level. A certain dissociation seems to be possible pharmacokinetically: structural modification of the corticosteroid molecule, especially introduction of suitable side chains, can lead to high concentrations of the active principal at the site of the desired effect and to low levels at the site of undesired effects. In the following, the most important pharmacokinetic properties of methylprednisolonaceponate (MPA), the active ingredient of Advantan® are presented: MPA is a di‐ester of the non‐halogenated methylprednisolone with a propionate group at C‐atom 17 and an acetate group at C‐atom 21. The introduction of both ester groups increase markedly the lipophilicity of the molecule and thus penetration into the skin. In addition the acetate side chain at C21 prevents a so‐called acyl‐migration of the propionic acid from C17 to C21 and thus stabilizes the molecule. After penetration out of the formulation into the living skin, MPA is hydrolized by the esterases in the epidermis and dermis at position 21, leading to the formation of methylprednisolone‐17‐propionate (MP‐17‐Prop). MP‐17‐Prop binds more strongly to the corticosteroid receptor than the parent substance MPA and represents the active principle in the skin. This so‐called ‘bioactivation’ proceeds distinctly faster in damaged and inflamed skin compared to healthy skin. After percutaneous absorption MP‐17‐Prop is inactivated by conjugation with glucuronic acid and is excreted mainly in the urine.