In vitro skin permeation studies are commonly used in the risk assessment of toxic compound skin exposure. The present study examined the utility of transepidermal water loss (TEWL) and electrical conductance as barrier integrity tests before skin permeation studies in vitro using a large number of skin samples and fentanyl. TEWL and conductance of the skin samples were measured before the permeation experiments in Franz diffusion cells in vitro with a vapometer and low voltage application, respectively. The data were analyzed based on the in vitro permeation results and in vivo skin absorption information from the transdermal fentanyl product labels. The results showed poor correlations between TEWL and electrical conductance for the skin samples. Weak correlations between fentanyl delivery rate (flux × area) and TEWL and skin conductance were observed. For comparison, TEWL and conductance were also examined after skin perturbation with a syringe needle, and both TEWL and conductance values of the skin samples increased after the perturbation. The data suggest that either TEWL of 10 g/m2/h or skin conductance of 0.07 mS/cm2 can be used as exclusion criteria in skin integrity testing to remove skin samples with high permeabilities under the in vitro conditions studied.

A variety of fundamental differences have evolved in the physiology of the human and rodent prolactin (PRL) systems. The PRL gene in humans and other primates contains an alternative promoter, 5.8 kbp upstream of the pituitary transcription start site, which drives expression of PRL in "extrapituitary" tissues, where PRL is believed to exert local, or paracrine, actions. Several of these extrapituitary PRL tissues serve a reproductive function (eg, mammary gland, decidua, prostate, etc), consistent with the hypothesis that local PRL production may be involved in, and required for, normal reproductive physiology in primates. Rodent research models have generated significant findings regarding the role of PRL in reproduction. Specifically, disruption (knockout) of either the PRL gene or its receptor causes profound female reproductive defects at several levels (ovaries, preimplantation endometrium, mammary glands). However, the rodent PRL gene differs significantly from the human, most notably lacking the alternative promoter. Understanding of the physiological regulation and function of extrapituitary PRL has been limited by the absence of a readily accessible experimental model, because the rodent PRL gene does not contain the alternative promoter. To overcome these limitations, we have generated mice that have been "humanized" with regard to the structural gene and tissue expression of PRL. Here, we present the characterization of these animals, demonstrating that the human PRL transgene is responsive to known physiological regulators both in vitro and in vivo. More importantly, the expression of the human PRL transgene is able to rescue the reproductive defects observed in mouse PRL knockout (mPRL(-)) females, validating their usefulness in studying the function or regulation of this hormone in a manner that is relevant to human physiology.

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