Pharmacokinetic profile of orally administered itraconazole in human skin

Itraconazole is an orally effective antifungal agent with a high affinity for tissues. The skin kinetics in human volunteers have been studied after administration of 100 and 200 mg of itraconazole daily. From day 7 onward, tissue levels in the beard region and on the back were consistently higher than the corresponding plasma levels. The levels in the palmar stratum corneum were lower than the corresponding plasma levels but persisted for 3 weeks after discontinuation of therapy. Stratum corneum levels in the beard area were still measurable 4 weeks after the end of therapy. With the 200-mg dose, sweat levels became detectable 24 hours after the first drug intake. The sweat levels were usually lower than the corresponding plasma levels and followed the same curve as the plasma levels. Sebum levels of itraconazole were 10 times as high as the corresponding peak plasma levels. Sebum levels were undetectable 14 days after discontinuation of therapy. The results indicate that oral intake of itraconazole will result in therapeutic levels in the skin and these levels vary, depending on the region of skin tested. There are at least three routes of delivery of itraconazole to the skin: (1) passive uptake by keratinocytes in the basal layer (as shown by the continued presence of the drug in the palmar stratum corneum at a moment when plasma, sebum, and sweat levels are again undetectable); (2) a less significant excretion through the sweat glands (as shown by the lower drug levels compared with the plasma levels); and (3) a massive excretion through the sebaceous glands (as shown by the sebum levels compared with the plasma levels).