In vitro cutaneous biotransformation of propranolol

The metabolism of propranolol by human skin and by several cell preparations has been investigated in vitro. The major metabolites produced by human skin in organ culture and by keratinocytes were N-desisopropylpropranolol (DIP), propranolol glycol (GLY), and naphthoxylactic acid (NLA). Formation of GLY and NLA was linear with incubation time up to 6 d and was directly proportional to propranolol concentration. Fibroblasts and melanocytes also produced GLY and NLA, but appeared to have lower propranolol-biotransforming activity than keratinocytes. The three metabolites detected arise from side-chain oxidation of propranolol, and the use of specific enzyme inhibitors determined that monoamine oxidase and cytochrome P450 isozymes are involved in their formation. Aldehyde and alcohol dehydrogenases are also probably involved in the formation of NLA and GLY, but attempts to inhibit these enzyme systems were inconclusive, possibly due to the chemical instability of the intermediate aldehyde resulting from monoamine oxidase activity. No evidence was found for conjugation or ring oxidation by the skin or isolated cells. Induction of keratinocyte differentiation with Ca++ or phorbol ester treatment resulted in an increase of overall biotransformation and the NLA/GLY ratio.