Original Article

Journal of Investigative Dermatology (1992) 98, 310–314; doi:10.1111/1523-1747.ep12499784

Cutaneous Metabolism of Theophylline by the Human Skin

John I Ademola, Ronald C Wester and Howard I Maibach

Department of Dermatology, School of Medicine, University of California, San Francisco, California, U.S.A.

Received 30 August 1990; Accepted 21 November 1991.

Top

Abstract

Percutaneous absorption of theophylline in human skin from five sources was examined by use of flow-through in vitro diffusion system. The metabolites and unchanged drug were estimated by thin layer chromatography. Correlation was evident it in the percentage of the applied dose that diffused through the fly skin samples (range 2.8plusminus 0 5% 7.7 plusminus 0 8%); however the percentage of applied dose absorbed varied between different skin samples (range 3.6plusminus 0.9% – 334plusminus 2.4%). Between 0.2 plusminus 0.1% 4.6plusminus 02% of the doses applied were metabolized, and over 60% of the total metabolites formed diffused through the skin. The uptake and metabolism of th theophylline by microsomes obtained from four of the human skin samples were measured All preparations showed detectable activities for the metabolism of theophylline. Microsomal preparations from skin sources A, B, and E and B, C, and E bio transformed theophylline to 1,3,7 trimethyluric acid and 1,3 dimethyl uric acid, respectively, The activities of microsomes from skin samples C and E on the drupe produced the pharmacologically active metabolite 3 methylxanthine. The specific activities of the microsomes from skin sources A- E for the formation of 1,3 dimethyl uric acid and 3 methylxanthine varied fivefold. However the variation in specific activities of the was twofold (range 2.8plusminus 0.1 -6.2plusminus 0.5 pmol/min per mg protein). These metabolic data ma;y be of value in the development of transdermal theophylline systems. The results indicate that a high level of absorption enhancement will be required before transdermal theophylline preparations could produce therapeutic plasma concentrations.

Top

References

  1. Piafsky, KM, Ogilvie, RI: Dosage of theophylline in bronchial asthma. N Engl J Med 1975 292: 1218–1222,  | PubMed | ChemPort |
  2. Mahler, DA, Matthay, RA, Snyder, PE, Wells, CK, Loke, J: Sustained-release theophylline reduces dyspnea in nonreversible obstructive airway disease. Am Rev Respir Dis 1985 131: 22–25,  | PubMed | ChemPort |
  3. Barr, PA: Weaning very low birth weight infants from mechanical ventilation using intermittent mandatory ventilation and theophylline. Arch Dis Child 1976 53: 598–600,
  4. Davi, MJ, Sankanan, K, Simons, KJ: Physiologic changes induced by theophylline in the treatment of apnea in preterm infants. J Pediatr 1978 92: 91–95,  | PubMed | ChemPort |
  5. Lakshminarayan, S, Sahn, SA, Weil, JV: Effects of aminophylline on ventilatory respiratory responses in normal men. Am Rev Respir Dis 1978 117: 33–38,  | PubMed | ChemPort |
  6. Aubier, M, Roussos, C: Effects of theophylline on respiratory muscle function. Chest 1985 88: 915–975,  | PubMed |
  7. Bukowskyi, M: Theophylline: an overview. Rational drug therapy 1985 22: 1–5,
  8. Matthay, RA: Favourable cardiovascular effects of theophylline in Chronic obstructive pulmonary disease. Chest 1987 92: 22–26,
  9. Hasegawa, T, Takagi, K, Ogura, Y: Studies on the temporal variations in the pharmacokinetics and metabolism of theophylline. Chem Pharm Bull 1987 35: 2079–2084,  | PubMed | ChemPort |
  10. Vree, TB, Martea, M, Tiggeler, RGL, Hekster, YA, Hafkenscheid, JCM: Pharmakokinetics of theophyiline and its metabolites in a patient undergoing continuous ambulatory peritoneal dialysis. Clin Pharmacokinet 1988 15: 390–393,  | PubMed | ChemPort |
  11. Cornish, LH, Christman, A: A study of the metabolism of theobromine, theophylline and caffeine in man. J Biol Chem 1957 228: 315–323,  | PubMed |
  12. Birkette, DJ, Miners, JO: Atwood: Secondary metabolism of theophylline biotransformation products in man: rate of formation of 1-methyl uric acid. Br J Clin Pharmacol 1983 15: 117–119,  | PubMed |
  13. Jenne, JW, Wyze, E, Rood, FS, Macdonald, FM: Pharmcokinetics of theophylline. Clin Pharm Ther 1972 13: 349–360,  | ChemPort |
  14. Goerz, G: Animal models for cutaneous drug metabolizing enzymes. In: Maibach HI, Lowe NJ (eds.). Models in Dermatology 1987, III: Karger, Basel, pp 93–105,
  15. Bronaugh, RL: Determination of percutaneous absorption by in vitro techniques. In: Bronaugh RL, Maibach HI (eds.). Percutaneous Absorption in Dermatology 1985, 6: Marcel Dekker, New York, Basel, pp 267–279,  | ChemPort |
  16. Pham, M, Magdalou, J, Totis, M, Fournel-Gigleux, S, Siest, G, Hammock, BD: Characterisation of distinct forms of cytochromes P-450, epoxide metabolizing enzymes and UDP-glucuronosyltransferases in rat skin. Biochem Pharmacol 1989 38: 2187–2194,  | Article | PubMed | ISI | ChemPort |
  17. Bronaugh, RL, Stewart, RF, Storm, JE: Extent of cutaneous metabolism during percutaneous absorption of xenobiotics. Toxicol Appl Pharmacol 1989 99: 534–543,  | Article | PubMed | ChemPort |
  18. Berthou, F, Ratanasavanh, D, Alix, D, Carlhat, D, Richie, C, Gullouzo, A: Caffeine and theophylline metabolism in newborn and adult human hepatocytes; comparison with adult rat hepatocytes. Biochem Pharmcol 1988 37: 3691–3700,  | ChemPort |
  19. Arnaud, MJ: Products of metabolism of caffeine. In: Dewis PB (ed.). Caffeine Perspective from Recent Research 1984, Springer; Berlin, pp 3–38,
  20. Aranda, JV, Louridas, AT, Vitello, BV, Aldridge, PTA, Haber, R: Metabolism of theophylline to caffeine in human fetal liver. Science 1979 206: 1319–1321,  | PubMed | ChemPort |
  21. Lohman, SM, Miech, RE: Theophylline metabolism by the rat liver microsomal system. J Clin Pharmacol Exp Ther 1976 196: 213–225,
  22. Robson, RA, Matheus, AP, Miners, JU, McManus, ME, Meyer, UA, Hal, PM, Birkette, DJ: Characterisation of theophylline metabolism in human liver microsomes. Br J Clin Pharmacol 1987 24: 293–300,  | PubMed | ChemPort |
  23. Peck, CC, Conner, DP, Brenda, BJ: Outward transdermal migration of theophylline. Pharmacol Skin 1987 1: 201–208,
  24. Buss, D, Leopold, D, Smith, AP, Routeledge, PA: Determination of the plasma protein binding of theophylline in health. Br J Clin Pharmacol 1983 15: 399–405,  | PubMed | ChemPort |
  25. Cooper, ER: In: Mittal KL, Fendler EJ (eds.). Solution Behaviour of Surfactants 1982, 2: Plenum, New York, pp 1505–1516,  | ChemPort |
  26. Touitou, E, Fabin, B: Altered skin permeation of a highly lipophilic molecule: tetra hydrocannabind. Int J Pharm 1988 43: 17–22,  | Article | ChemPort |
  27. Caldwell, J, Lancaster, R, Monks, TJ, Smith, RL: The influence of dietary methylxanthines on the metabolism and pharmacokinetics of intravenously administered theophylline. Br J Clin Toxicol 1979 4: 637–638,
  28. Persson, CG, Anderson, KE: Respiratory and cardiovascular effects of 3-methylxanthines, a metabolite of theophylline. Acta Pharmacol Toxicol 1977 49: 529–536,
  29. Miller, M, Opheim, KE, Raisys, VA, Motulsky, AG: Theophylline metabolism: variation and genetics. Clin Pharm Ther 1984 35: 170–182,  | ChemPort |
  30. Bruce, JA, Blake, JA, Rogers, NJ, Hussain, MA: Transdermal oxymorphone formulation development and methods for evaluating flux and lag times for two skin permeation-enhancing vehicles. J Pharm Sciences 1990 79: 1072–1076,

Extra navigation

.
ADVERTISEMENT