Effect of receiver fluid pH on in vitro skin flux of weakly ionizable drugs.
In in vitro skin permeation experiments, the pH of viable epidermis is readily conditioned by the receiver fluid. For weakly ionizable compounds, the flux determined experimentally thus depends on the receiver fluid pH. The purpose of the present work is to characterize this pH effect, since nonphysiological conditions have often been used in the receiver fluid to enhance the solubility of the subject compounds. A transport model was developed to analyze the above-mentioned pH effect of the receiver fluid on the steady state flux of weakly ionizable drugs. The results showed that the skin flux had a strong dependence on pH for those compounds with high intrinsic partition coefficients. Experimentally, this pH effect was observed with a model acid and a model base. The skin flux was found to have a profound dependence on the receiver fluid pH. This dependence also correlates with the octanol/water partition coefficient of the molecule. It was concluded that the use of a physiological receiver fluid would be crucial for a realistic estimation of transdermal potential. The results also suggested that, for weakly ionizable compounds with high partition coefficients, the viable epidermis could be a significant transport barrier for systemic absorption.
Kou
J H
JH
Syntex Research, Palo Alto, California 94304.
Roy
S D
SD
Du
J
J
Fujiki
J
J
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005079:Excipients; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008567:Membranes, Artificial; D008954:Models, Biological; D008970:Molecular Weight; D009529:Nicardipine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D010599:Pharmacokinetics; D012867:Skin / Q000737:chemistry*; D012869:Skin Absorption / Q000502:physiology*; D012995:Solubility; D012997:Solvents
D005079:Excipients; D008567:Membranes, Artificial; D012997:Solvents; D009529:Nicardipine