Quinine distribution in mice withplasmodium berghei malaria

  • Eric Pussard
  • Alexandra Bernier
  • Elyane Fouquet
  • Patrice Bouree


The disposition of a single 80 mg/kg injection of quinine base was compared in control andPlasmodium berghei-infected mice. Pharmacokinetic parameters were determined on repeated whole blood samples from caudal vein (experiment 1) and quinine distribution was evaluated in tissues and blood fractions from mice sacrificed two hours post dosing (experiment 2). Quinine concentrations were assessed by high performance liquid chromatography with fluorometric detection. Whole blood concentrations and AUC0−∞ of quinine increased in a parasitaemia-dependent manner. Quinine blood clearance and peak blood concentrations of metabolites negatively correlated with the parasitaemia. The apparent distribution volume of quinine only decreased in severely ill mice.

Quinine concentrations rise in a parasitaemia-dependent manner in homogenates of spleen, lungs and kidney and in erythrocyte pellets. The negative relationship, observed between the parasitaemia and the tissue-to-whole blood ratio for muscle, heart, liver and brain, contributes to the reduction of the blood distribution volume. Quinine uptake by muscle and heart was dependent on the free fraction of plasma quinine. The liver and brain concentrations of quinine were similar in control and infected mice. The tissue-to-plasma free fraction ratios decrease when the parasitaemia rises suggesting a restrictive uptake of quinine by these tissues. In conclusion.P. berghei malaria decreases both total clearance and apparent volume of distribution with a heterogeneous redistribution of quinine between the tissues.


Plasmodium berghei malaria mice quinine pharmacokinetics tissue distribution 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    White N.J., Chanthavanich P., Krishna S., Bunch C. and Silamut K. (1983): Quinine disposition kinetics. Br. J. Clin. Pharmacol., 16, 399–403.PubMedGoogle Scholar
  2. 2.
    White N.J., Looareesuwan S., Warrell D.A., Warrell M.J., Bunnag D. and Harinasuta T. (1982): Quinine pharmacokinetics and toxicity in cerebral and uncomplicatedfalciparum malaria. Am. J. Med., 73, 564–572.CrossRefPubMedGoogle Scholar
  3. 3.
    Pussard E., Barennes H., Daouda H., Clavier F., Mahaman Sani A., Osse M., Granic G. and Verdier F. (1999): Quinine disposition in globally malnourished children with cerebral malaria. Clin. Pharmacol. Ther., 65, 500–510.CrossRefPubMedGoogle Scholar
  4. 4.
    Krishna S. and White N.J. (1996): Pharmacokinetics of quinine, chloroquine and amodiaquine: clinical implications. Clin. Pharmacokinet., 30, 263–299.CrossRefPubMedGoogle Scholar
  5. 5.
    Emudianughe T.S., Bickle Q.D., Taylor M.G. and Andrews B. (1985): Effect ofplasmodium berghei infection on benzoic acid metabolism in mice. Experientia, 41, 1407–1409.CrossRefPubMedGoogle Scholar
  6. 6.
    Mansor S.M., Edwards G., Roberts P.J. and Ward S.A. (1991): The effect of malaria infection on paracetamol disposition in the rat. Biochem. Pharmacol., 41, 1701–1711.CrossRefGoogle Scholar
  7. 7.
    Mansor S.M., Ward S.A. and Edwards G. (1991): The effect of malaria infection on antipyrine metabolite formation in the rat. Biochem. Pharmacol., 41, 1264–1266.CrossRefPubMedGoogle Scholar
  8. 8.
    Wilairatana P., Looareesuwan S., Vanijanonta S., Charoenlarp P. and Wittayalertpanya S. (1994): Hepatic metabolism in severefalciparum malaria: caffeine clearance study. Ann. Trop. Med. Parasitol., 88, 13–19.PubMedGoogle Scholar
  9. 9.
    Mansor S.M., Ward S.A., Edwards G., Hoaksey P.E. and Breckenridge A.M. (1990): The effect of malaria infection on the disposition of quinine and quinidine in the rat isolated perfused liver preparation. J. Pharm. Pharmacol., 42, 428–432.PubMedGoogle Scholar
  10. 10.
    Song G.H., Andre R.G., Scheibel L.W., Wirtz R.A., Cheriathundam E. and Alvares A.P. (1995):Plasmodium berghei: sensitivity of chloroquine-resistant and chloroquine-sensitive strains to irradiation and the effect of irradiated parasites on cytochrome P450-dependent monooxygenases. Res. Com. Mol. Path. Pharmacol., 90, 75–85.Google Scholar
  11. 11.
    Saxena N., Saxena A., Dutta G.P., Gatak S. and Pandey V.C. (1987): Effect ofPlasmodium yoleii nigeriensis infection and chloroquine on the hepatic mixed function oxidase system of mice. Mol. Biochem. Parasitol., 24, 283–287.CrossRefPubMedGoogle Scholar
  12. 12.
    Pukrittayakamee S., Looareesuwan S., Keeratithakul D., Davis T.M.E., Teja-Isavadharm P., Nagachinta B., Weber A., Smith A.L., Kyle D. and White N.J. (1997): A study of the factors affecting the metabolic clearance of quinine in malaria. Eur. J. Clin. Pharmacol., 52, 487–493.CrossRefPubMedGoogle Scholar
  13. 13.
    Silamut K., White N.J., Looareesuwan S. and Warrell D.A. (1985): Binding of quinine to plasma proteins infalciparum malaria. Am. J. Trop. Med. Hyg., 34, 681–686.PubMedGoogle Scholar
  14. 14.
    Peters W. (1987): Chemotherapy and drug resistance in malaria. 2nd Edition. Academic Press. London.Google Scholar
  15. 15.
    Thumwood C.M., Hunt N.H., Clark I.A. and Cowden W.B. (1988): Break down of the blood-brain barrier in murine cerebral malaria. Parasitology 96, 579–589.CrossRefPubMedGoogle Scholar
  16. 16.
    Brown H., Hien T.T., Day N., Mai N.T., Chuong L.V., Chau T.T., Loc P.P., Phu N.H., Bethell D., Farrar J., Gatter K., White N.J. and Turner G. (1999): Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol. Appl. Neurobiol., 25, 331–340.CrossRefPubMedGoogle Scholar
  17. 17.
    Brown H.C., Chau T.T.C., Mai N.T.H., Day N.P.J., Sinh D.X., White N.J., Hien T.T., Farrar J. and Turner G.D.H. (2000): Blood-brain barrier function in cerebral malaria and CNS infections in Vietnam. Neurology, 55, 104–111.PubMedGoogle Scholar
  18. 18.
    Vuong P.N., Richard F., Snounou G., Coquelin F., Rénia L., Gonnet F., Chabaud A.G. and Landau I. (1999): Development of irreversible lesions in the brain, heart and kidney following acute and chronic murine malaria infection. Parasitology, 119, 546–553.CrossRefGoogle Scholar
  19. 19.
    Zhao H.J. and Ishizaki T. (1997): Thein vitro hepatic metabolism of quinine in mice, rats and dogs: comparison with human liver microsomes. J. Pharmacol. Exp. Ther., 283, 1168–1176.PubMedGoogle Scholar
  20. 20.
    Iliadis A., Brown C. and Huggins M.L. (1992): Apis: a software for model identification, simulation and dosage regimens calculation in clinical and experimental pharmacokinetics. Comp. Methods Programs Biomed. 38, 227–239.CrossRefGoogle Scholar
  21. 21.
    Zhang H., Coville P.F., Walker R.J., Miners J.O., Birkett D.J. and Wanwimolruk S. (1997): Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine. Br. J. Clin. Pharmacol., 43, 245–252.CrossRefPubMedGoogle Scholar
  22. 22.
    Liddle C., Graham G.G., Christopher R.K., Bhuwapathanapun S. and Duffield A.M. (1981). Identification of new urinary metabolites in man of quinine using methane chemical ionization gas chromatography-mass spectrometry. Xenobiotica, 11, 81–87.CrossRefPubMedGoogle Scholar
  23. 23.
    Wanwimolruk S., Wong S.M., Zhang H. and Coville P.F. (1996): Simultaneous determination of quinine and a major metabolite 3-hydroxy quinine in biological fluids by HPLC without extraction. J. Liq. Chromatogr., 19, 293–305.CrossRefGoogle Scholar
  24. 24.
    Bannon P., Yu P., Cook J.M., Roy L. and Villeneuve J.P. (1998): Identification of quinine metabolites in urine after oral dosing in humans. J. Chromatogr., 715, 387–393.CrossRefGoogle Scholar
  25. 25.
    Muller-Eberhard U., Eiseman J.L., Foielart M. and Alvares A.P. (1983): Effect of heme on allylisopropyl acetamide induced changes in heme and drug metabolism in the rhesus monkey (Macaca mulatta). Biochem. Pharmacol., 32, 3763–3769.Google Scholar
  26. 26.
    Bertini R., Bianchi M., Villa P. and Ghezzi P. (1988): Depression of liver drug metabolism and increase in plasma fibrinogen by interleukin 1 and tumor necrosis factor: a comparison with lymphotoxin and interferon. Int. J. Immunopharmacol., 10, 525–530.CrossRefPubMedGoogle Scholar
  27. 27.
    Monshouwer M., McLellan R.A., Delaporte E., Witkamp R.F., van Miert A. and Renton K.W. (1996): Differential effect of pentoxifylline on lipopolysaccharide-induced downregulation of cytochrome P450. Biochem. Pharmacol., 52, 1195–1200.CrossRefPubMedGoogle Scholar
  28. 28.
    Pukrittayakamee S., White N.J., Davis T.M., Looareesuwan S., Supanaranond W., Desakorn V., Chaivisuth B. and Williamson D.H. (1992): Hepatic blood flow and metabolism in severefalciparum malaria: clearance of intravenously administered galactose. Clin. Sci., 82, 63–70.PubMedGoogle Scholar
  29. 29.
    Mansor S.M., Molyneux M.E., Taylor T.E., Ward S.A., Wirima J.J. and Edwards G. (1991): Effect ofPlasmodium falciparum malaria infection on the plasma concentration of α1-acid glycoprotein and the binding of quinine in Malawian children. Br. J. Clin. Pharmacol., 32, 317–321.PubMedGoogle Scholar
  30. 30.
    Mansor S.M., Ward S.A., Edwards G., Hoakey P.E. and Breckenridge A.M. (1991): The influence of α1-acid Glycoprotein on quinine disposition in the rat isolated perfused liver preparation J. Pharm. Pharmacol., 43, 650–654.PubMedGoogle Scholar
  31. 31.
    Rimchala P., Karbwang J., Sukontason K., Banmairuroi V., Molunto P. and Na-Bangchang K. (1996): Pharmacokinetics of quinine in patients with chronic renal failure. Eur. J. Clin. Pharmacol., 49, 497–501.CrossRefPubMedGoogle Scholar
  32. 32.
    Ceithami J. and Evans E.A. (1946): The biochemistry of the malaria parasite. VII.In vitro studies of the distribution of quinine between blood cells and their suspending medium. Arch. Biochem. Biophys., 10, 397–416.Google Scholar
  33. 33.
    Salako L.A. and Ajayi F.O. (1987): Distribution and urinary excretion of the desethylmetabolites of chloroquine in the rat. J. Pharm. Pharmacol., 39, 859–860.PubMedGoogle Scholar
  34. 34.
    Mackey L.J., Hochmann A., June C.H., Contreras C.E. and Lambert P.H. (1980): Immunopathological aspects ofPlasmodium berghei infection in five strains of mice. II. Immunopathology of cerebral and other tissues lesions during the infection. Clin. Exp. immunol., 42, 412–420.PubMedGoogle Scholar
  35. 35.
    Karbwang J., Davis T.M., Looareesuwan S., Molunto P., Bunnag D. and White N.J. (1993): A comparison of the pharmacokinetic and pharmacodynamic properties of quinine and quinidine in healthy Thai males. Br. J. Clin. Pharmacol., 35, 265–71.PubMedGoogle Scholar
  36. 36.
    Rodriguez-Acosta A., Finol H.J., Pulido-Mendez M., Marquez A., Andrade A., Gonzalez N., Aguilar I., Giron M.E. and Pinto A. (1998): Liver ultrastructural pathology in mice infected withPlasmodium berghei. J. Submicrosc. Cytol. Pathol., 30, 299–307.Google Scholar
  37. 37.
    Neill A.L. and Hunt N.H. (1992): Pathology of fatal and resolvingPlasmodium berghei cerebral malaria in mice. Parasitology, 105, 165–175.CrossRefPubMedGoogle Scholar
  38. 38.
    Kusuhara H., Suzuki H., Terasaki T., Kakee A., Lemaire M. and Sugiyama Y. (1997): P-Glycoprotein mediates the efflux of quinidine across the blood-brain barrier. J. Pharmacol. Exp. Ther., 283, 574–580.PubMedGoogle Scholar
  39. 39.
    Fromm M.F. (2000): P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int. J. Clin. Pharmacol. Ther., 38, 69–74.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Eric Pussard
    • 2
  • Alexandra Bernier
    • 2
  • Elyane Fouquet
    • 1
  • Patrice Bouree
    • 1
  1. 1.Service de ParasitologieHôpital de BicêtreLe Kremlin-BicêtreFrance
  2. 2.Service de PharmacologieHôpital de BicêtreLe Kremlin-BicêtreFrance

Personalised recommendations