Distribution and metabolism of topically applied progesterone in a rat model.

This study investigated the transdermal uptake and subsequent tissue distribution of [(3)H]progesterone applied in a commercially available progesterone cream in a rat model. Concentrations of lipid- and water-soluble metabolites of [(3)H]progesterone were also measured in plasma, urine and selected tissues (uterus, liver, kidney, salivary gland) 3 h after its topical application. Female rats were ovariectomized and adrenalectomized to remove all endogenous progesterone, and 4 weeks later were anaesthetized and 150 mg Pro-Feme cream (containing progesterone 3.2% w/w and 200 microCi [(3)H]progesterone) was applied to the abdominal skin. Six arterial blood samples were then obtained from a carotid cannula over the following 3h, and urine and selected tissue samples were collected after the final blood sample. Plasma progesterone increased progressively until 90 min, then remained relatively stable. Plasma levels of [(3H)]progesterone were high by the 15-min sample and increased only slightly thereafter. Water-soluble metabolites were detectable in plasma at 15 min, whereas lipid-soluble metabolites became apparent only by 60 min then increased progressively to 180 min. The tissue:plasma concentration ratio for [(3)H]progesterone exceeded 1 in all tissues, most notably in uterus (8.4) and lung (9.6), whereas urinary [(3)H]progesterone levels were only half those in plasma. Concentrations of lipid- and water-soluble progesterone metabolites were most prevalent in liver and kidney, and both reached very high concentrations in urine. These results demonstrate that topically applied progesterone is rapidly absorbed transdermally and that its patterns of distribution and metabolism are comparable to those previously reported for intravascularly administered progesterone.