Relationships between skin permeability and physicochemical properties of drugs were examined to establish a predictive method for the steady-state permeation rate of drugs through human skin. Human skin permeation properties fell into two categories: one in which the permeability coefficient is correlated to the partition coefficient, revealed with lipophilic drugs; and the other in which the permeability coefficients are almost constant, shown with hydrophilic drugs. The stratum corneum, the main barrier in skin, could be considered as a membrane with two parallel permeation pathways: lipid and pore pathways, and an equation for predicting the steady-state permeation rate of drugs was derived. The skin permeabilities of drugs for man were compared with those for hairless rat. The species difference in skin permeability found was suggested to be due to the difference in skin permeation pathways, since lipid content and water uptake of the stratum corneum varied between human and hairless rat skin.

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Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique pharmacokinetic characteristics among the members of this class. Many in vivo and in vitro human and animal studies suggest that active transport mechanisms are involved in the pharmacokinetics of pravastatin. The oral bioavailability of pravastatin is low because of incomplete absorption and a first-pass effect. The drug is rapidly absorbed from the upper part of the small intestine, probably via proton-coupled carrier-mediated transport, and then taken up by the liver by a sodium-independent bile acid transporter. About half of the pravastatin that reaches the liver via the portal vein is extracted by the liver, and this hepatic extraction is mainly attributed to biliary excretion which is performed by a primary active transport mechanism. The major metabolites are produced by chemical degradation in the stomach rather than by cytochrome P450-dependent metabolism in the liver. The intact drug and its metabolites are cleared through both hepatic and renal routes, and tubular secretion is a predominant mechanism in renal excretion. The dual routes of pravastatin elimination reduce the need for dosage adjustment if the function of either the liver or kidney is impaired, and also reduce the possibility of drug interactions compared with other statins. which are largely eliminated by metabolism. The lower protein binding than other statins weakens the tendency for displacement of highly protein-bound drugs. Although all statins show a hepatoselective disposition, the mechanism for pravastatin is different from that of the others. There is high uptake of pravastatin by the liver via an active transport mechanism, but not by other tissues because of its hydrophilicity, whereas the disposition characteristics of other statins result from high hepatic extraction because of high lipophilicity. These pharmacokinetic properties of pravastatin may be the result of the drug being given in the pharmacologically active open hydroxy acid form and the fact that its hydrophilicity is markedly higher than that of other statins. The nature of the pravastatin transporters, particularly in humans, remains unknown at present. Further mechanistic studies are required to establish the pharmacokinetic-pharmacodynamic relationships of pravastatin and to provide the optimal therapeutic efficacy for various types of patients with hypercholesterolaemia.

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Skin age is one of the biological factors affecting percutaneous absorption. 1,2) To regulate the therapeutic efficacy of transdermal drug delivery, the difference in skin permeability at various ages is a subject of considerable importance. We previously reported that the permeability through the skin decreases with aging, 3,4) and that the extent of this decrease is higher for lipophilic permeants than for hydrophilic permeants. 4) We clarified that the thickness of skin strata is an important factor for limited percutaneous absorption in aging. However, other physiological changes in the skin with age, e.g., moisture content in the skin, lipid composition, lipid content, dermis thickness, and density of skin appendages, have been also reported. [5][6][7][8] Therefore the age-related differences in the skin barrier function must be further investigated based on physiological alterations in the skin to elucidate the mechanisms of the age dependency of transdermal absorption of drugs.There have been many reports on age-related changes in the transdermal permeation of drugs, 3,4,[6][7][8][9] however, age-related changes in skin permeability have not been fully interpreted because of large interindividual variance and the limited number of model permeants. Recently, it was reported that impedance parameters can sensitively reflect the properties of skin permeation pathways. [10][11][12] The impedance technique enables us to determine rapidly changes in skin physical properties, and one measurement provides information on pathways for both hydrophilic and lipophilic permeants. Therefore skin impedance analysis may be a useful method to elucidate the skin barrier function at different ages.In the present study, we attempted to apply impedance analysis to investigate age-dependent changes in permeation pathways of rat skin. In vitro skin impedance data of rats at various ages were compared. Physiological characteristics of the skin, e.g., the water and lipid content of the stratum corneum and the thickness of the skin strata, were also evaluated. Finally, we demonstrated the age dependency of relations between these electrical and physiological properties. MATERIALS AND METHODS AnimalsMale STD: Wistar rats at the age of 5, 10, 21, 90, and 180 d (Japan SLC Inc., Hamamatsu, Japan) were used. Rats were fed commercial food pellets and tap water ad libitum. Under sodium pentobarbital anesthesia (50 mg/kg, i.p.), a round section of the abdominal skin was excised, and then the subcutaneous fat and other extraneous tissue were trimmed off carefully. The skin sample was immediately used in the following skin impedance experiments.Skin Impedance Measurement and Analysis A sideby-side, two-chamber electrochemical cell with four electrodes, two for supplying current and two for recording signals, was designed according to the procedure of Burnett and Bagniefski.11) The rat skin was mounted in an O-ring seal between the two chambers, each having 23 ml volume and 1 cm 2 exposed area. The current-supplying electrode consisted of 0....