Absorption of indomethacin and its calcium salt through rat skin: effect of penetration enhancers and relationship between in vivo and in vitro penetration.
The in vivo percutaneous absorption and in vitro penetration of indomethacin (IND) and the calcium salt (IND-Ca) in ointments were investigated on rat abdominal skin under occlusions in the presence or absence of penetration enhancers. The absorption of IND-Ca from the gel (Hiviswako) ointment was significantly higher than that from a standard ointment of IND, an approximation of a commercial product. Sorbitan monooleate had no enhancer effect for the IND-Ca gel ointment, while the addition of calcium thioglycolate dramatically decreased the absorption of IND-Ca due to powdering of the ointment. The absorption of drugs was significantly increased by adding Azone in the gel ointment resulting in an approximate 3-fold increase in the parameters, Cmax and AUC. The percutaneous absorption of drugs from white petrolatum base was relatively lower than that from gel ointment. The plasma IND concentrations after a topical application of the gel ointments for 6 h (3.0 cm X 3.0 cm area, 1.0 g of 5% IND ointment) were over the therapeutically effective concentrations during 48 h. The bioavailability of IND after application of ointments was 9.1-27.8% for the gel base and 4.5-6.3% for the white petrolatum base. The in vitro penetration behavior of drugs using a Franz diffusion cell resembled the result of the in vivo absorption more closely. The relationship between the in vitro (the permeability coefficient and skin/ointment partition coefficient) and in vivo (Cmax and AUC) penetration parameters was linear and there was a clear correlation between both parameters.
D000818:Animals; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006601:Hexoses / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009824:Ointments; D019946:Propylene Glycol; D011409:Propylene Glycols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012869:Skin Absorption / Q000187:drug effects; D013864:Thioglycolates / Q000494:pharmacology
D006601:Hexoses; D009824:Ointments; D011409:Propylene Glycols; D013864:Thioglycolates; C018665:sorbitan monooleate; D019946:Propylene Glycol; C017487:2-mercaptoacetate; D002118:Calcium; D007213:Indomethacin; D004121:Dimethyl Sulfoxide