Correlation of aqueous and lipid solubilities with flux for prodrugs of 5-fluorouracil, theophylline, and 6-mercaptopurine: A Potts-Guy approach.
The Potts and Guy equation that has been used to predict permeability coefficients for molecules being delivered from aqueous vehicles has been transformed to accommodate lipid vehicles that are less polar than skin, and polar vehicles that are less polar than water. Solubilities in pH 4.0 aqueous buffer (SAQ), solubilities in isopropyl myristate (SIPM), and molecular weights (MW) of prodrugs of 5-fluorouracil (5-FU), theophylline (Th), and 6-mercaptopurine (6-MP) have been regressed against their fluxes from suspensions in IPM (JM). Seven series (n = 39) of alkylcarbonyloxymethyl (ACOM), alkyloxycarbonyl (AOC), alkylcarbonyl (AC), and alkylaminocarbonyl (AAC) prodrugs were used to determine the best fit to the transformed Potts and Guy equation (eq 6): log JM = x + y log SIPM + (1 - y)log SAQ - z MW. The estimated values for x, y, and z were -0. 193, +0.525, and +0.00364, respectively, with r 2 = 0.945 for n = 39. Inclusion of a miscellaneous series comprised of the parent drugs and a branched alkyl chain prodrug gave an equally good fit only if 6-MP was excluded from the analysis. The best performer (largest JM) in each series was usually correctly identified. The values for x, y, and z were consistent with values obtained by Potts and Guy, but the inclusion of the (l - y)log SAQ term in eq 6 and the value for y, shows that water solubility is almost as important as lipid solubility in predicting flux. There were no significant changes in predicted log JM or xi for each series if their log JM or xi were calculated using y and z coefficients obtained for solutions to eq 6 from which the data for the series had been excluded. This suggests that the data from all the series is homogeneous. Data from Kasting, Smith, and Cooper for SIPM, SPG, and MW of unrelated molecules were regressed against their fluxes from propylene glycol (PG) using eq 7: log JM = x + y log SIPM + (1 - y) log SPG - z MW. The estimated values for x, y, and z were -1.673, +0.599, and +0.00595, respectively, with r 2 = 0.852 for n = 28. These values for x, y, and z are also consistent with those previously reported by Potts and Guy, and, together with the results for fluxes from IPM, show the general utility of the transformed Potts and Guy equation in predicting flux from vehicles other than water and in showing the importance of solubility in a polar solvent as well as a nonpolar solvent in predicting flux.
Roberts
W J
WJ
Department of Medicinal Chemistry, P.O. Box 100485, University of Florida, Gainesville, Florida 32610, USA.
Sloan
K B
KB
D005472:Fluorouracil / Q000737:chemistry*; D015122:Mercaptopurine / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility; D013806:Theophylline / Q000737:chemistry*
D011355:Prodrugs; D013806:Theophylline; D015122:Mercaptopurine; D005472:Fluorouracil