Despite much research into the mechanisms of cutaneous aging and the identification of significant age-associated biological and biophysical changes within the skin, the question "How does aging affect percutaneous absorption (PA) in vivo?" remains unanswered. We have made in vivo measurements of PA in young (18-40 years) and old (greater than 65 years) subjects. Standard radiotracer methodology was employed and PA was quantified from the urinary excretion profiles of 14C radiolabel (corrected for incomplete renal elimination). Testosterone (TST), estradiol (EST), hydrocortisone (HC), benzoic acid (BA), acetylsalicylic acid (ASA), and caffeine (CAFF) have been studied. Permeation of HC, BA, ASA, and CAFF was significantly (p less than 0.01, 0.01, 0.01, and 0.05, respectively) lower in aged subjects, whereas the absorption of TST and EST was similar in the two groups. Thus it appears that aging can affect PA in vivo and that relatively hydrophilic compounds are particularly sensitive. The diminished surface lipid content of "old" skin implies a diminished dissolution medium for compounds administered topically. It is reasonable to speculate that this physiologic change will impact most severely upon those permeants whose lipid solubility is lowest (that is, HC, BA, ASA, CAFF). Furthermore, the typically reduced hydration of aged stratum corneum will compound this effect for these chemicals. Conversely, highly lipid-soluble chemicals (TST and EST) may still be able to dissolve readily into the stratum corneum even when the available lipid medium is reduced.
To probe age-related changes in skin barrier function, transepidermal water loss (TEWL) rates have been measured in "young" (19-42 years) and "old" (69-85 years) subjects. TEWL was determined at ventral forearm skin sites, which had been occluded for 24 hr with polypropylene chambers. Baseline TEWL rates (J infinity), which showed no dependence on age, were measured for each subject before and after the experiment. Following removal of the occlusive chamber, TEWL was monitored continuously from t = 0.5 min until its return to the baseline (preocclusion) level, which was typically in the range of 2-7 g/m2/hr. Initial TEWL rates (mean +/- SD) were found to differ significantly between young (28.6 +/- 7.5 g/m2/hr; n = 26) and old (36.9 +/- 10.5 g/m2/hr; n = 18) subjects (P less than 0.01). Relaxation of TEWL to J infinity was significantly slower in the aged cohort, such that the characteristic time for diffusion of water in the stratum corneum was estimated to be (mean +/- SD) 176 +/- 59 min for the young subjects, compared to 360 +/- 76 min for the old (P less than 0.001.). Thus, the initial TEWL value following removal of occlusion is significantly greater, and the excessive stratum corneum hydration produced by occlusion is dissipated more slowly, in old skin than in young. A hypothesis to explain the slower relaxation of perturbed TEWL in old skin is proposed.
The penetration of drugs through aged skin is important both in terms of transdermal delivery to elicit systemic pharmacological effects, and for topical treatment. Cutaneous microcirculation efficiency, an integral parameter in the overall process of percutaneous absorption, was studied in young (20-34 years) and old (64-86 years) individuals. Cutaneous erythema as induced by topical administration of methyl nicotinate to the ventral forearm, was monitored non-invasively using laser-Doppler flowmetry. Dose-response behaviour was characterized by five parameters: (i) the time of onset of action; (ii) the time to reach maximum response; (iii) the magnitude of the maximum response; (iv) the area under the response-time curve; and (v) the time to decay to 75% of the maximum response. Additionally, the sensitivity and efficiency of the cutaneous microcirculation in both age groups was evaluated using a pharmacokinetic-pharmacodynamic model. Statistical analysis of all data showed no significant differences between the age groups for the same concentrations. The results indicate that microvessel reactivity to the applied stimulus is comparable in the ventral forearm of both young and old populations.
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