After dermal application of 1023 μg/cm2 equivalents, IR3535® was slowly cleared from rat skin with

an approximately 50% reduction in residual concentration occuring over a time period of 48 h. The identity of the radioactivity remaining in skin was not determined. The metabolite IR3535®-free acid 2 is expected to be exclusively excreted with urine due to its high polarity and molecular weight well below the threshold for biliary elimination in humans GSK-3 inhibition (MW 550 Da). Moreover, IR3535®1 is of insufficient volatility to be cleared to a larger extent by exhalation. The data on plasma concentrations show a rapid absorption and excretion of dermally applied IR3535® since the concentration of IR3535®-free acid 2 in plasma already decreases after 4 h and reaches the LOQ at the 24 h sampling point. Despite applying very similar doses of IR3535® to the skin and almost identical mean recoveries of IR3535®-free acid 2 in urine, peak plasma concentrations of IR3535®-free acid 2 were twofold higher in male human subjects as compared to the female humans subjects in the study. The basis for these differences is not known and may be due to gender differences

in absorption, distribution, AZD4547 mw and biotransformation of IR3535®. Due to the rapid absorption and elimination, the recovered amount of IR3535®-free acid 2 in urine represents the extent of absorption of IR3535®1 through the skin in humans. Absorption of IR3535®1 in humans therefore is 13.3% ( Table 6) which is less than half of that observed

through the skin in experimental animals or in vitro. The formulation contains the known skin penetration enhancers ethanol, PEG-8 and PEG-32 at concentrations of 35.0, 5.0 and 4.0%, respectively ( Table Clomifene 1). Therefore, the determined penetration rate of 13.3% for IR3535 can reasonably be considered as a worst-case value for skin absorption. Thomas H. Broschard, Anja M. Bohlmann and Stefan Konietzny are employees from Merck KGaA, which is a producer of IR3535®. This study was supported by Merck KGaA, Darmstadt, Germany. The authors thank Jutta zur Lage, Nataly Bittner, Heike Keim-Heusler, and Ursula Tatsch for excellent technical assistance. “
“The authors regret an error in the captions for Figs. 10 and 11 in the abovementioned published paper. ‘DMP1(-IRE)’ should have read ‘DMT1(-IRE)’ throughout. Corrected captions for Figures 10 and 11 are given below. Fig. 10 Effect of Pb exposure on DMT1(-IRE) and FP1 expression in the cerebral cortex samples through immunohistochemistry. Immunohistochemical images of the temporal area of the cerebral cortex demonstrated the expression of DMT1(-IRE) and FP1 (scale bar = 100 μm). (A) Immunohistochemistry with the DMT1(-IRE) and FP1 antibodies in the temporal area of the cerebral cortex. (B) Quantification of the protein levels is represented as the mean IOD in the temporal and parietal areas of the cerebral cortex. Values represent means ± S.E.M.s.