Metabolismand clearance of proxicromil — Studies in rat, hamster, rabbit, dog, squirrel monkey, cynomolgus monkey, baboon and man

  • Dennis A. Smith
  • Michael G. Neale


Proxicromil was extensively metabolized and eliminated as metabolites in urine and faeces by the rat, hamster, rabbit, squirrel monkey, cynomolgus monkey, baboon and man after oral administration. The pathway of metabolism in these species was by hydroxylation of the alicyclic ring principally to yield monohydroxylated metabolites with trace amounts of a dihydroxylated product. Elimination of proxicromil by the dog, however, was essentially as the unchanged drug. The lack of metabolism of the drug by the dog resulted in the dog having a dependence on biliary excretion of the unchanged drug for clearance. These differences in clearance routes between species were reflected in the plasma clearance of the drug. The value for rat, a species capable of metabolism, was approximately 20 fold (4.1 ml min−1kg−1) greater than the corresponding value for dog (0.2 mlmin−1kg−1). Inhibiting the metabolism of proxicromil in the rat with SKF-525A lowered plasma clearance of proxicromil (0.6 ml min−1kg−1) and elevated the proportion of unchanged drug cleared by biliary excretion.

Key words

proxicromil metabolism and clearance 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Augstein, J., Cairns, H., Hunter, D., Lee, T.B., Suschitzky, J., Altounyan, R.E.C., Jackson, D.M., Mann, J., Orr, T.S.C. and Sheard, P. (1977). New orally effective chromone derivatives for the treatment of asthma. Agents and Actions,7, 443–445.CrossRefPubMedGoogle Scholar
  2. 2.
    Bamford, D.G., Clark, B., Clarke, A.J., Smith, D.A. and Tattersall, M.L. (1980): Safety evaluation studies on proxicromil, an orally effective anti-allergy compound. Toxicol. Letts.,1000. 172.Google Scholar
  3. 3.
    Bamford, D.G., Clark, B., Clarke, A.J. and Tattersall, M.L. (1980): Oral toxicity of proxicromil, an antiallergy compound in five species. Toxicol. Letts.,1000, 48.Google Scholar
  4. 4.
    Smith, D.A. (1976): The determination and characterization of diacetylmorphine (heroin) and its metabolism. Ph.D. Thesis, Manchester University.Google Scholar
  5. 5.
    Buhring, K.U., Diekmann, H.W., Miller, H., Garbe, A. and Nowak, H. (1978): Metabolism of praziquantel in man. Eur. J. Drug Metab. Pharmacokinet.,3, 179–190.Google Scholar
  6. 6.
    Drayer, D.E. and Reidenberg, M.M. (1973): Metabolism of tetralin and toxicity of cuprex in man. Drug Metab. and Disp.,1, 577–579.Google Scholar
  7. 7.
    Elliott, T.H. and Hanam, J. (1968): The metabolism of tetralin. Biochem. J.,108, 551–559.PubMedGoogle Scholar
  8. 8.
    Fonseka, K. and Widman, M. (1977): Dihydroxylated metabolites of cannabinol formed by rat liverin vitro. J. Pharm. Pharmacol.,29, 12–14.PubMedGoogle Scholar
  9. 9.
    Hawkins, D.R., Moore, D.H. and Chasseaud, L.F. (1977): The metabolism of the neuroleptic agent l-(4’-flurophenyl)-4-(cyclohexyl-l’-piperazinyl-4’-carbo- xylate)-butan-l-one hydrochloride in rats and man. Xenobiotica,7, 315–325.CrossRefPubMedGoogle Scholar
  10. 10.
    May, H.E., Boose, R. and Reed, D.J. (1974): Hydroxylation of the carcinostatic 1-(2-chloroethyl)-3-cy-clohexyl-1-nitrosourea (CCNU) by rat liver microsomes. Biochem. Biophys. Res. Commun.,57, 426–433.CrossRefPubMedGoogle Scholar
  11. 11.
    Nation, R.L., Triggs, E.J. and Vine, J. (1978): Metabolism and urinary excretion of benzhexol in humans. Xenobiotica,8, 165–169.CrossRefPubMedGoogle Scholar
  12. 12.
    Testa, B. and Jenner, P. (1976): The concept of regioselectivity in drug metabolism. J. Pharm. Pharmac,28, 731–744.Google Scholar
  13. 13.
    Dayton, P.G., Cunningham, R.F. and Wwiner, I.M. (1973): Studies on the fate of metabolites and analogs of probenecid. Drug Metab. Disp.,1, 742–751.Google Scholar
  14. 14.
    Gros, P.M., Dari, H.J., Chasseaud, L.F. and Hawkins, D.R. (1974): Metabolic and pharmacokinetic study of bucloxic acid. Arzneim-Forsch,24, 1385–1389.Google Scholar
  15. 16.
    Zacchei, A.G., Wishousky, T.I. and Watson, L.S. (1978): The physiological disposition of (2-cyclopentyl-6,7-dichloro-2 methyl-l-oxo-5 indanyloxyjacetic acid in the rat, dog, rherus monkey and baboon. Drug Metab. Disp.,6, 313–320.Google Scholar

Copyright information

© Springer-Verlag 1983

Authors and Affiliations

  • Dennis A. Smith
    • 1
  • Michael G. Neale
    • 1
  1. 1.Department of Metabolic Studies, PLC Limited — Pharmaceutical DivisionResearch and Development LaboratoriesLoughborough, LeicestershireUK

Personalised recommendations