Abstract
Purpose. Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate.
Methods. The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate.
Results. Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate.
Conclusions. The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.
Similar content being viewed by others
REFERENCES
P. Singh and M. S. Roberts. Dermal and underlying tissue pharmacokinetics of salicylic acid after topical application. J. Pharmacokin. Biopharm. 21:337-373 (1993).
P. Singh and M. S. Roberts. Skin permeability and local tissue concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) after topical application. J. Pharmacol. Exp. Ther. 268:141-151 (1994).
P. Singh and M. S. Roberts. Dermal and underlying tissue pharmacokinetics of lidocaine after topical application. J. Pharm. Sci. 83:773-782 (1994).
P. Singh and M. S. Roberts. Effects of vasoconstriction on dermal pharmacokinetics and local tissue distribution of compounds. J. Pharm. Sci. 83:783-791 (1994).
P. Singh and M. S. Roberts. Deep tissue penetration of bases and steroids after dermal application in rat. J. Pharm. Pharmacol. 46:956-964 (1994).
P. Singh and M. S. Roberts. Local deep tissue penetration of compounds after dermal application: Structure-tissue Penetration Relationships. J. Pharmacol. Exp. Ther. 279:908-917 (1997).
P. Singh, H. I. Maibach, and M. S. Roberts. Site of effects. In Roberts, M. S., Walters, K. A. (eds) Dermal Absorption and Toxicity Assessment. Marcel Dekker, New York, pp. 353-370 (1998).
S. E. Cross, C. Anderson, M. J. Thompson, and M. S. Roberts. Is there tissue penetration after application of topical salicylate formulations? Lancet 350:636 (1997).
S. E. Cross, C. Anderson, and M. S. Roberts. Assessment of direct penetration of commercial salicylate esters and salts using isolated human skin and clinical microdialysis studies. Br. J. Clin. Pharmacol. 46:29-35 (1998).
M. S. Roberts and K. A. Walters. The relationship between structure and barrier function of skin. In Roberts, M. S., Walters, K. A. (eds) Dermal Absorption and Toxicity Assessment. Marcel Dekker, New York, pp. 1-42 (1998).
H. Ishihama, H. Kimata, and Y. Mizushima. Percutaneous penetration of indomethacin. Experientia 35:798-799 (1979).
Y. Wada, Y. Etoh, A. Ohira, H. Kimata, T. Koide, H. Ishihama, and Y. Mizushima. Percutaneous absorption and anti-inflammatory activity of indomethacin in ointment. J. Pharm. Pharmacol. 34:467-468 (1982).
U. Giese. Absorption and distribution of ibuprofen from a cream formulation after dermal administration to guinea pigs. Arzneim. Forsch. 40:84-88 (1990).
S. C. McNeill, R. O. Potts, and M. L. Francoeur. Local enhanced topical delivery of drugs: Does it really exist? Pharm. Res. 9:1422-1427 (1992).
J. L. Rabinowitz, E. S. Feldman, A. Weinberger, and H. R. Schumacher. Comparative tissue absorption of oral 14C-salicylate in humans and canine knee joints. J. Clin. Pharmacol. 22:42-48 (1982).
J. R. Baldwin, R. A. Carrano, and A. R. Imondi. Penetration of trolamine salicylate into the skeletal muscle of pig. J. Pharm. Sci. 73:1002-1004 (1984).
V. W. Riess, K. Schmid, L. Botta, K. Kobayashi, J. Moppert, W. Schneider, A. Sioufi, A. Strusberg, and M. Tomasi. Die perkutane resorption von diclofenac. Arzneim. Forsch./Drug. Res. 36:1092-1096 (1986).
J. Radermacher, D. Jentsch, M. A. Scholl, T. Lustinetz, and J. C. Frolich. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br. J. Clin. Pharmacol. 31:537-541 (1991).
M. Dawson, C. M. McGee, J. H. Vine, P. Nash, T. R. Watson, and P. M. Brooks. The disposition of biphenylacetic acid following topical application. Eur. J. Clin. Pharmacol. 33:639-642 (1988).
D. F. McCafferty and A. D. Woolfson. New patch delivery system for percutaneous local anaesthesia. Br. J. Anaesth. 71:370-374 (1993).
N. V. Sheth, M. B. McKeough, and S. L. Spruance. Measurement of the stratum corneum drug reservoir to predict the therapeutic efficacy of topical indodeoxyuridine for herpes simplex virus infection. J. Invest. Dermatol. 89:598-602 (1987).
D. Dupis, A. Rougier, R. Roguet, C. Lotte, and G. Kalopissis. In vivo relationship between horny layer reservoir effect and percutaneous absorption in human and rat. J. Invest. Dermatol. 82:353-356 (1984).
S. M. Wallace, H. M. Falkenberg, J. O. Runikis, and W. D. Stewart. Skin levels and vasoconstrictor assay of topically applied hydrocortisone. Arch. Dermatol. 115:440-441 (1979).
S. E. Cross, Z. Y. Wu, and M. S. Roberts. Effect of perfusion flow rate on the tissue uptake of solutes after dermal application using the isolated perfused rat hindlimb preparation. J. Pharm. Pharmacol. 46:844-850 (1994).
S. E. Cross, Z. Y. Wu, and M. S. Roberts. The effect of protein binding on the deep tissue penetration and efflux of dermally applied salicylic acid, lignocaine and diazepam in the perfused rat hindlimb. J. Pharmacol. Exp. Ther. 277:366-374 (1996).
Z. Y. Wu, L. P. Smithers, and M. S. Roberts. Physiological pharmacokinetics of solutes in perfused rat hindlimb: Characterisation of the physiology with changing perfusate flow, protein content and temperature using statistical moment analysis. J. Pharmacokin. Biopharm. 21:653-688 (1993).
Z. Y. Wu, S. E. Cross, and M. S. Roberts. Influence of physicochemical parameters and perfusate flow rate on the distribution of solutes in the isolated perfused rat hindlimb determined by the impulse-response technique. J. Pharm. Sci. 84:1020-1027 (1995).
M. Rowland and T. N. Tozer. Clinical Pharmacokinetics: Concepts and Applications, 2nd edn., Lea & Febiger, Philadelphia pp. 34-47 (1989).
D. C. Brater. Pocket Manual of Drug Use in Clinical Medicine, 4th edition B. C. Decker Inc: Toronto (1989)
Z. Y. Wu, B. M. Smithers, and M. S. Roberts. Tissue and perfusate pharmacokinetics of melphalan in isolated perfused rat hindlimb. J. Pharmacol. Exp. Ther. 282:1131-1138 (1997).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Roberts, M.S., Cross, S.E. A Physiological Pharmacokinetic Model for Solute Disposition in Tissues Below a Topical Application Site. Pharm Res 16, 1392–1398 (1999). https://doi.org/10.1023/A:1018998908655
Issue Date:
DOI: https://doi.org/10.1023/A:1018998908655