The effect of water solubility of solutes on their flux through human skin in vitro: a prodrug database integrated into the extended Flynn database

Int J Pharm. 2008 Mar 3;351(1-2):92-103. doi: 10.1016/j.ijpharm.2007.09.034. Epub 2007 Sep 29.

Abstract

A database (n=50) consisting of values of solubility in water, S AQ, solubility in octanol, S OCT, molecular weight, MW, and maximum flux based on the delivery of total species containing a parent drug by its prodrugs through human skin in vitro from water has been integrated into the extended Flynn database (n=114). In addition, data for two more recent contributions (n=8) and one (n=7) contribution that was overlooked for inclusion in the extended Flynn database were added to the prodrug database, as well as the data for the parent drugs (n=6), to give n=71 and n=185 for the total integrated database. This integrated database was fit to five equations where the independent variable was S AQ, S OCT or MW alone or were combinations of S OCT and MW (Kasting-Smith-Cooper, KSC model) or S OCT, S AQ and MW (Roberts-Sloan, RS model). The RS equation gave the best fit: log J MAQ=-2.506+0.538 log S OCT+0.462 log S AQ-0.00402MW, r2=0.839, S.D.=0.423 and the residual (Delta log J MAQ) was 0.474 log units. Integration of a substantial number of prodrugs into the extended Flynn database did not change the dependence of J MAQ on a balance of S AQ and S OCT. No trend in the effect of the prodrug being more or less water soluble than its parent drug on over- or underpredicting flux (+/-Delta'log J MAQ) by the RS model was found. Thus optimization of the S AQ of a prodrug in its design, as well as the design of new drugs, is indicated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Octanol
  • Databases, Factual
  • Humans
  • In Vitro Techniques
  • Molecular Weight
  • Permeability
  • Prodrugs / chemistry*
  • Skin / metabolism
  • Skin Absorption*
  • Solubility
  • Solvents / chemistry*
  • Water / chemistry

Substances

  • Prodrugs
  • Solvents
  • Water
  • 1-Octanol