Skip to main content
SpringerLink
Log in

Percutaneous Absorption and Metabolism of Lonapalene in Psoriatic Skin

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

The percutaneous absorption and metabolism of lonapalene (6-chloro-2,3-dimethoxynaphthalene-1,4-diol-diacetate; RS-43179), a topically effective 5-lipoxygenase inhibitor, has been measured in six subjects with stable plaque-type psoriasis of the lower extremities. Lonapalene readily penetrates psoriatic skin, is rapidly and completely metabolized, and is almost entirely excreted in the urine. Unexpectedly we observed a trend for thigh (T) plaque skin to be more permeable than lower leg (LL) plaque skin as measured by total absorption (T, 44.8 ± 13.4%; LL, 24.9 ± 12.6% applied dose excreted), peak plasma levels (T, 209 ± 107; LL, 146 ± 81 ng Eq/ ml), and peak rate of urinary excretion (T, 591.7 ± 112.2; LL, 318.4 ± 143.9 µg Eq/hr). There were also differences in the metabolic profiles between the two sites as measured by the quantity and proportion of dealkylated and conjugated products excreted in the urine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. D. V. K. Murthy, M. Kruseman-Aretz, S. Rouhafza-Fard, C. J. Bedord, J. M. Young, G. Jones, and M. Venuti. Selective inhibitors of arachidonic acid (AA) 5-lipoxygenase by a novel antipsoriatic agent 6-chlorol,4-,-diacetoxy-2,3-dimethoxynap-thalene (RS 43179). Fed. Proc. 44:886 (1985).

    Google Scholar 

  2. A. K. Black, R. D. R. Camp, A. I. Mallet, F. M. Cunningham, M. Hofbauer, and M. W. Greaves. Pharmacologic and clinical effects of lonapalene (RS 43179), a 5-lipoxygenase inhibitor, in psoriasis. J. Invest. Dermatol. 95:50–54 (1990).

    Google Scholar 

  3. C. T. Jansen, K. Lammintausta, R. E. S. Bullingham, and S. Forsstrom. A clinical trial of lonapalene, fluocinolone acetonide and vehicle in psoriasis. J. Invest. Dermatol 86:483 (1986).

    Google Scholar 

  4. A. Lassus and S. Forsstrom. A dimethoxynapthalene derivative (RS 43179 gel) compared with 0.025% Fluocinolone acetonide gel in the treatment of psoriasis. Br. J. Dermatol. 113:103–106 (1985).

    Google Scholar 

  5. K. Fogh, T. Herlin, and K. Kragballe. Eicosanoids in acute and chronic psoriatic lesions: Leukotriene B4, but not 12-hydroxy-eicosatetraenoic acid, is present in biologically active amounts in acute guttate lesions. J. Invest. Dermatol. 92:837–841 (1989).

    Google Scholar 

  6. E. A. Duell, C. N. Ellis, and J. J. Voorhees. Determination of 5, 12, and 15-lipoxygenase products in keratomed biopsies of normal and psoriatic skin. J. Invest. Dermatol. 91:446–450 (1988).

    Google Scholar 

  7. S. D. Brain, R. D. R. Camp, A. K. Black, P. M. Dowd, M. W. Greaves, A. W. Ford-Hutchinson, and S. Charleston. Leukotrienes C4 and D4 in psoriatic skin lesions. Prostaglandins 29:611–619 (1985).

    Google Scholar 

  8. R. Camp, R. Russel Jones, S. Brain, P. Woollard, and M. Breaves. Production of intraepidermal microabscesses by topical application of leukotriene B4. J. Invest. Dermatol. 82:202–204 (1984).

    Google Scholar 

  9. F. W. Bauer, P. C. M. van de Kerkhof, and R. M. Maassen-De Grood. Epidermal hyperproliferation following the induction of microabscesses by leukotriene B 4. Br. J. Dermatol. 115:409–412 (1986).

    Google Scholar 

  10. J. J. Voorhees. Leukotrienes and other lipoxygenase products in the pathogenesis and therapy of psoriasis and other dermatoses. Arch. Dermatol. 119:541–547 (1982).

    Google Scholar 

  11. H. Degrees, P. Dockx, P. DeDoncker, K. DeBeule and G. Cauwenbergh. A double-blind vehicle-controlled study of R 68151 in psoriasis: A topical 5-lipoxygenase inhibitor. J. Am. Acad. Dermatol. 22:751–755 (1990)

    Google Scholar 

  12. T. J. Franz. Percutaneous absorption: on the relevance of invitro data. J. Invest. Dermatol. 64:190–195 (1975)

    Google Scholar 

  13. T. J. Franz and P. A. Lehman. The use of water permeability as a means of validation for skin integrity in in vitro percutaneous absorption studies. J. Invest. Dermatol. 94(4):525 (1990).

    Google Scholar 

  14. T. J. Franz. Kinetics of cutaneous drug penetration. Int. J Dermatol. 22(9):499–505 (1983).

    Google Scholar 

  15. T. J. Franz and P. A. Lehman. Systemic absorption of retinoic acid. J. Toxicol.-Cut. Ocul. Toxicol. 8(4):1–10 (1989).

    Google Scholar 

  16. R. J. Feldmann and H. I. Maibach. Regional variation in percutaneous penetration of 14C cortisol in man. J. Invest. Dermatol. 48(2):181–183 (1967)

    Google Scholar 

  17. H. I. Maibach, R. J. Feldmann, T. Milby, and W. Serat. Regional variation in percutaneous penetration in man. Arch. Environ. Health 23:208–211 (1971)

    Google Scholar 

  18. F. J. Marzulli. Barriers to skin penetration. J. Invest. Dermatol. 39:387–393 (1962).

    Google Scholar 

  19. A. Rougier and C. Lotte. Correlations between horny layer concentration and percutaneous absorption. Pharmacol. Skin 1:81–102 (1987).

    Google Scholar 

  20. D. M. Lantz, P. A. Lehman, and T. J. Franz. Regional variation in percutaneous absorption. J. Invest. Dermatol. 92(3):466 (1989).

    Google Scholar 

  21. R. B. Stoughton. Percutaneous absorption of drugs. Annu. Rev. Pharmacol. Toxicol. 29:55–69 (1989).

    Google Scholar 

  22. J. Serup. Non-invasive quantification of psoriasis plaques-measurements of skin thickness with 15 mHz pulsed ultrasounds. Clin. Exp. Dermatol. 9:502–508 (1984).

    Google Scholar 

  23. H. Tagami, Y. Kanamaru, K Inoue, S. Suehisa, F. Inoue, K. Iwatsuki, K. Yoshikuni, and M. Yamada. Water sorption-desorption test of the skin in vivo for functional assessment of the stratum corneum. J. Invest. Dermatol. 78:425–428 (1982).

    Google Scholar 

  24. E. Berardesca and H. I. Maibach. Noninvasive bioengineering assessment of psoriasis. Int. J. Dermatol. 28(3):157–160 (1989).

    Google Scholar 

  25. J. C. T. Wang, B. G. Patel, C. W. Ehmann, and N. Lowe. The release and percutaneous permeation of anthralin products, using clinically involved and uninvolved psoriatic skin. J. Am. Acad. Dermatol. 16:812–821 (1987).

    Google Scholar 

  26. R. C. Wester, D. A. W. Bucks, and H. I. Maibach. In vivo percutaneous absorption of hydrocortisone in psoriatic patients and normal volunteers. J. Am. Acad. Dermatol. 8:645–647 (1983).

    Google Scholar 

  27. T. J. Franz, P. A. Lehman, and L. McGuire: In vivo methods for the assessment of percutaneous absorption in man. In J. Zatz (ed.), Percutaneous Absorption, Allured Wheaton, IL, 1992.

    Google Scholar 

  28. P. K. Noonan and R. C. Wester. Cutaneous metabolism of xenobiotics. In R. L. Bronaugh and H. I. Maibach (eds.), Percutaneous Absorption, 2nd ed., Marcel Dekker, New York, 1989, pp. 53–75.

    Google Scholar 

  29. M. Pham, J. Magdalou, G. Siest, M. Lenoir, B. A. Bernard, J. Jamoulle, and B. Shroot. Reconstituted epidermis: A novel model for the study of drug metabolism in human epidermis. J. Invest. Dermatol. 94:749–752 (1990).

    Google Scholar 

  30. J. E. Storm, S. W. Collier, R. F. Stewart, and R. L. Bronaugh. Metabolism of xenobiotics during percutaneous penetration: Role of absorption rate and cutaneous enzyme activity. Fund. Appl. Toxicol. 15:132–141 (1990).

    Google Scholar 

  31. W. A. Khan, S. S. Park, H. V. Gelboin, D. R. Bickers, and H. Mukhtar. Monoclonal antibodies directed characterization of epidermal and hepatic cytochrome P-450 isozymes induced by skin application of therapeutic crude coal tar. J. Invest. Dermatol. 93:40–45 (1989).

    Google Scholar 

  32. M. E. Stewart, P. E. Pochi, J. S. Strauss, H. H. Wotiz, and S. J. Clark. In vitro metabolism of [3H]testosterone by scalp and back skin: Conversion of testosterone into 5-androstane-3β,17β-diol. J. Endocr. 72:385–390 (1977).

    Google Scholar 

  33. J. D. Wilson and J. D. Walker. The conversion of testosterone to 5-androstan-17β-ol-3-one (diydrotestosterone) by skin slices of man. J. Clin. Invest. 48:371–379 (1969).

    Google Scholar 

  34. G. Santus, N. Watari, R. S. Hinz, L. Z. Benet, and R. H. Guy. Cutaneous metabolism of transdermally delivered nitroglycerin in vitro. Pharmacol. Skin 1:240–244 (1987).

    Google Scholar 

  35. P. H. Chapman, M. D. Rawlins, and S. Shuster. Activity of aryl hydrocarbon hydroxylase in psoriatic skin. Lancet 1:297–298 (1979).

    Google Scholar 

  36. S. Shuster, M. D. Rawlins, P. H. Chapman, and S. Rogers. Decreased epidermal aryl hydrocarbon hydroxylase and localized pustular psoriasis. Br. J. Dermatol. 103:23–26 (1980).

    Google Scholar 

  37. D. Bickers, H. Mukhtar, T. Dutia-Choudhury, C. Marcelo, and J. Voorhees. Epidermal drug metabolism in human subjects: Comparative activity in normal individuals and patients with psoriasis. Clin. Res. 30(2):260A (1982).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Dermatology, School of Medicine, University of Washington, Seattle, Washington, 98115

    Paul A. Lehman & John E. Olerud

  2. Department of Dermatology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, Arkansas, 72205

    Paul A. Lehman, Jerry I. Johnson & Thomas J. Franz

  3. Syntex Research, Palo Alto, California, 94304

    Raymond V. Tomlinson & William A. Akers

Authors
  1. Paul A. Lehman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raymond V. Tomlinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerry I. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John E. Olerud
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William A. Akers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas J. Franz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lehman, P.A., Tomlinson, R.V., Johnson, J.I. et al. Percutaneous Absorption and Metabolism of Lonapalene in Psoriatic Skin. Pharm Res 9, 1145–1151 (1992). https://doi.org/10.1023/A:1015843503746

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1015843503746

Search

Navigation