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Topical Delivery of 5-Fluorouracil and 6-Mercaptopurine by Their Alkylcarbonyloxymethyl Prodrugs from Water: Vehicle Effects on Design of Prodrugs

Pharmaceutical Research volume 20, pages 639–645 (2003)Cite this article

Abstract

Purpose. To determine whether the fluxes through hairless mouse skin for three homologous series of prodrugs of 5-fluorouracil (5-FU, 1) and 6-mercaptopurine (6-MP, 2) from saturated aqueous suspensions show dependencies on aqueous (S AQ) and isopropyl myristate (S IPM) solubilities similar to those shown by the identical compounds delivered from IPM.

Methods. Flux through hairless mouse skin from water (J MAQ) and solubility data were measured for a homologous series of six 3-alkylcarbonyloxymethyl (ACOM) prodrugs of 5-FU (3-ACOM-5-FU), and five 6-ACOM-6-MP prodrugs, then combined with literature data for five bis-6,9-ACOM-6-MP prodrugs to give a data base. Multiple linear regression using SPSS 7.5 was performed on log S IPM, log S AQ, molecular weight and log J MAQ data to determine the best fit coefficients to the transformed Potts-Guy equation: log J MAQ = x + y log S IPM + (1 - y) log S AQ + z MW. Permeability coefficients (P MAQ) were calculated from J MAQ/S AQ.

Results. The best fit coefficients for the flux from AQ(J MAQ)were x = -1.497, y = 0.660 and z = -0.00469 (r 2 = 0.765) with an average error of prediction equal to 0.193 log units. The best fit coefficients for the flux from IPM (J MIPM) were x = -0.557, y = 0.536 and z = -0.00261 (r 2 = 0.941) with an average error of prediction equal to 0.109 log units. For all three series, log P MAQ increased whereas log P MIPM decreased with increasing alkyl chain lengths in the promoiety and with decreasing solubility parameter values.

Conclusions. The transformed Potts-Guy equation can be used to predict J MAQ but with less certainty than J MIPM. S IPM and S AQ have consistently been shown to have a positive influence on J MIPM, and now on J MAQ, with a balance between the two solubilities being obviously important. The previous observation that log P MAQ increased with lipophilicity is an artifact of normalizing J MAQ by S AQ.

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REFERENCES

  1. B. W. Barry. Dermatological Formulations: Percutaneous Absorption. Marcel Dekker, New York, 1983.

    Google Scholar 

  2. D. W. Osborne and A. H. Amann. Topical Drug Delivery Formulations, Marcel Dekker, New York, 1990.

    Google Scholar 

  3. R. P. Waranis and K. B. Sloan. The effect of vehicle and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: bisacyloxymethyl-6-mercaptopurine prodrugs. J. Pharm. Sci. 76:587-595 (1987).

    Google Scholar 

  4. R. P. Waranis and K. B. Sloan. Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: S6-acyloxymethyl-6-mercaptopurine prodrugs. J. Pharm. Sci. 77:210-215 (1988).

    Google Scholar 

  5. W. J. Roberts and K. B. Sloan. Correlation of aqueous and lipid solubilities with flux for prodrugs of 5-fluorouracil, theophylline and 6-mercaptopurine: A Potts-Guy approach. J. Pharm. Sci. 88:515-532 (1999).

    Google Scholar 

  6. W. J. Roberts and K. B. Sloan. Prediction of transdermal flux of prodrugs of 5-fluorouracil, theophylline and 6-mercaptopurine with a series/parallel model. J. Pharm. Sci. 89:1415-1431 (2000).

    Google Scholar 

  7. R. O. Potts and R. H. Guy. Predicting skin permeability. Pharm. Res. 9:663-669 (1992).

    Google Scholar 

  8. B. P. Wenkers and B. C. Lippold. Skin penetration of nonsteroidal antiinflammatory drugs out of a lipophilic vehicle: influence of the viable epidermis. J. Pharm. Sci. 88:1326-1331 (1999).

    Google Scholar 

  9. W. J. Roberts and K. B. Sloan. Application of the transformed Potts-Guy equation to in vivo human skin data. J. Pharm. Sci. 90:1318-1323 (2001).

    Google Scholar 

  10. W. J. Roberts and K. B. Sloan. Synthesis of 3-alkylcarbonyloxymethyl derivatives of 5-fluorouracil. J. Het. Chem. 39:905-910 (2002).

    Google Scholar 

  11. H. D. Beall and K. B. Sloan. Topical delivery of 5-fluorouracil (5-FU) by 3-alkylcarbonyl-5-FU prodrug. Int. J. Pharm. 217:127-137 (2001).

    Google Scholar 

  12. W. J. Roberts and K. B. Sloan. Topical delivery of 5-fluorouracil(5-FU) by 3-alkylcarbonyloxymethyl-5-FU prodrugs. J. Pharm. Sci. 92:1028-1036 (2003).

    Google Scholar 

  13. K. B. Sloan, S. A. M. Koch, K. G. Siver, and F. P. Flowers. The use of solubility parameters of drug and vehicle to predict flux. J. Invest. Dermatol. 87:244-252 (1986).

    Google Scholar 

  14. K. B. Sloan, H. D. Beall, W. R. Weimar, and R. Villaneuva. The effect of receptor phase composition on the permeability of hairless mouse skin in diffusion cell experiments. Int. J. Pharm. 73:97-104 (1991).

    Google Scholar 

  15. R. F. Fedors. A method for estimating both the solubility parameters and molar volumes of liquids. Polym. Eng. Sci. 14:147-154 (1974).

    Google Scholar 

  16. Martin, P. L. Wu, and T. Velasquez. Extended Hildebrand solubility approach: sulfonamides in binary and ternary solvents. J. Pharm. Sci. 74:277-282 (1985).

    Google Scholar 

  17. D. J. W. Grant and T. Higuchi. Solubility Behavior of Organic Compounds. John Wiley and Sons, New York, 89-133 (1990).

    Google Scholar 

  18. T. Higuchi. Physical chemical analyses of percutaneous absorption process from creams and ointments. J. Soc. Cosmet. Chem. 18:85-97 (1960).

    Google Scholar 

  19. K. B. Sloan, S. A. M. Koch, and K. G. Siver. Mannich base derivatives of theophylline and 5-fluorouracil: Syntheses, properties and topical delivery characteristics. Int. J. Pharm. 21:251-264 (1984).

    Google Scholar 

  20. J. Hadgraft and W. J. Pugh. The selection and design of topical and transdermal agents: A review. J. Invest. Dermatol. Symp. Proc. 3:131-135 (1998).

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicinal Chemistry, University of Florida, P.O. Box 100485, Gainesville, Florida, 32610

    Kenneth B. Sloan, Scott Wasdo, Udo Ezike-Mkparu, Thomas Murray, Donna Nickels, Surjit Singh, Thea Shanks, John Tovar, Karen Ulmer & Robert Waranis

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  1. Kenneth B. Sloan
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  2. Scott Wasdo
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Correspondence to Kenneth B. Sloan.

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Sloan, K.B., Wasdo, S., Ezike-Mkparu, U. et al. Topical Delivery of 5-Fluorouracil and 6-Mercaptopurine by Their Alkylcarbonyloxymethyl Prodrugs from Water: Vehicle Effects on Design of Prodrugs. Pharm Res 20, 639–645 (2003). https://doi.org/10.1023/A:1023207118209

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  • DOI: https://doi.org/10.1023/A:1023207118209

  • water solubility
  • lipid solubility
  • diffusion cell experiments
  • transformed Potts-Guy equation
  • flux
  • prodrugs