Clinical Pharmacokinetics

, Volume 39, Issue 4, pp 255–270 | Cite as

Pharmacokinetics of Artemisinin-Type Compounds

  • Visweswaran Navaratnam
  • Sharif Mahsufi Mansor
  • Nam-Weng Sit
  • James Grace
  • Qigui Li
  • Piero Olliaro
Review Articles Drug Disposition

Abstract

Various compounds of the artemisinin family are currently used for the treatment of patients with malaria worldwide. They are characterised by a short half-life and feature the most rapidly acting antimalarial drugs to date. They are increasingly being used, often in combination with other drugs, although our knowledge of their main pharmacological features (including their absorption, distribution, metabolism and excretion) is still incomplete. Such data are particularly important in the case of combinations. Artemisinin derivatives are converted primarily, but to different extents, to the bioactive metabolite artenimol after either parenteral or gastrointestinal administration. The rate of conversion is lowest for artelinic acid (designed to protect the molecule against metabolism) and highest for the water-soluble artesunate. The absolute and relative bioavailability of these compounds has been established in animals, but not in humans, with the exception of artesunate. Oral bioavailability in animals ranges, approximately, between 19 and 35%. A first-pass effect is highly probably for all compounds when administered orally. Artemisinin compounds bind selectively to malaria-infected erythrocytes to yet unidentified targets. They also bind modestly to human plasma proteins, ranging from 43% for artenimol to 81.5% for artelinic acid.

Their mode of action is still not completely understood, although different theories have been proposed. The lipid-soluble artemether and artemotil are released slowly when administered intramuscularly because of the ‘depot’ effect related to the oil formulation. Understanding the pharmacokinetic profile of these 2 drugs helps us to explain the characteristics of the toxicity and neurotoxicity. The water-soluble artesunate is rapidly converted to artenimol at rates that vary with the route of administration, but the processes need to be characterised further, including the relative contribution of pH and enzymes in tissues, blood and liver. This paper intends to summarise contemporary knowledge of the pharmacokinetics of this class of compounds and highlight areas that need further research.

References

  1. 1.
    Luo XD, Shen CC. The chemistry, pharmacology, and clinical applications of qinghaosu (artemisinin) and its derivatives. Med Res Rev 1987; 7: 29–52.PubMedCrossRefGoogle Scholar
  2. 2.
    Barradell LB, Fitton A. Artesunate: a review of its pharmacology and therapeutic efficacy in treatment of malaria. Drugs 1995: 50(4): 714–41.PubMedCrossRefGoogle Scholar
  3. 3.
    de Vries PJ, Dien TK. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 1996; 52(6): 818–36.PubMedCrossRefGoogle Scholar
  4. 4.
    Smith DA, van de Waterbeemd H. Pharmacokinetics and metabolism in early drug discovery. Curr Opin Chem Biol 1999; 3: 373–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Maggs JL, Madden S, Bishop LP, et al. The rat biliary excretion of dihydroartemisinin, an antimalarial endoperoxide. Drug Metab Dispos 1997; 25(10): 1200–4.PubMedGoogle Scholar
  6. 6.
    Batty KT, Ilett KF, Edwards G, et al. Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes. Br J Pharmacol 1998; 125(1): 159–67.PubMedCrossRefGoogle Scholar
  7. 7.
    White NJ, van Vugt M, Ezzet F. Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 1999; 37(2): 105–25.PubMedCrossRefGoogle Scholar
  8. 8.
    Titulaer HA, Zuidema J, Kager PA, et al. The pharmacokinetics of artemisinin after oral, intramuscular and rectal administration to volunteers. J Pharm Pharmacol 1990; 42(11): 810–3.PubMedCrossRefGoogle Scholar
  9. 9.
    Ashton M, Gordi T, Trinh Nh, et al. Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses. Biopharm Drug Dispos 1998; 19: 245–50.PubMedCrossRefGoogle Scholar
  10. 10.
    Sidhu JS, Ashton M, Huong NV, et al. Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria. Br J Clin Pharmacol 1998; 45: 347–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Ashton M, Sy ND, Van Huong N, et al. Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria. Clin Pharmacol Ther 1998; 63(4): 482–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Koopmans R, Duc DD, Kager PA, et al. The pharmacokinetics of artemisinin suppositories in Vietnamese patients with malaria. Trans R Soc Trop Med Hyg 1998; 92: 434–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Koopmans R, Ha LD, Duc DD, et al. The pharmacokinetics of artemisinin after administration of two different suppositories to healthy Vietnamese subjects. Am J Trop Med Hyg 1999; 60: 244–7.PubMedGoogle Scholar
  14. 14.
    Navaratnam V, Mansor SM, Mordi MN, et al. Comparative pharmacokinetic study of oral and rectal formulations of artesunic acid in healthy volunteers. Eur J Clin Pharmacol 1998; 54: 411–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Looareesuwan S, Wilairatana P. The rational use of qinghaosu and its derivatives: what is the future of new compounds? Med Trop 1998; 58 Suppl. 3: 89S–92S.Google Scholar
  16. 16.
    Li GQ, Wang XH, Gui XB, et al. Dose findings of dihydroartemisinin in treatment of falciparum malaria. Southeast Asian J Trop Med Public Health 1999; 30(1): 17–9.PubMedGoogle Scholar
  17. 17.
    Wilairatana P, Chanthavanich P, Singhasivanon P, et al. A comparison of three different dihydroartemisinin formulations for the treatment of acute uncomplicated falciparum malaria in Thailand. Int J Parasitol 1998; 28: 1213–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Looareesuwan S, Wilairatana P, Vanijanonta S, et al. Treatment of acute, uncomplicated falciparum malaria with oral dihydroartemisinin. Ann Trop Med Parasitol 1996; 90: 21–8.PubMedGoogle Scholar
  19. 19.
    Li Q-G, Peggins JO, Fleckenstein LL, et al. The pharmacokinetics and bioavailability of dihydroartemisinin arteether, artemether, artesunic and arteline acid in rats. J Pharm Pharmacol 1998; 50: 173–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Melendez V, Peggins JO, Brewer TG, et al. Determination of the antimalarial arteether and its deethylated metabolite dihydroartemisinin in plasma by high-performance liquid chromatography with reductive electrochemical detection. J Pharmacol Sci 1991; 80: 132–8.CrossRefGoogle Scholar
  21. 21.
    Li Q-G, Brueckner RP, Peggins JO, et al. Arteether toxicokinetics and pharmacokinetics in rats after 25 mg/kg/day single and multiple doses. Eur J Drug Metab Pharmacokinet 1999; 24(3): 213–23.PubMedCrossRefGoogle Scholar
  22. 22.
    Benakis A, Paris M, Plessas C, et al. Pharmacokinetics of sodium artesunate after im and iv administration [abstract]. Am J Trop Med Hyg 1993; 49 Suppl.: 293.Google Scholar
  23. 23.
    Batty KT, Thu LT, Davis TM, et al. A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria. Br J Clin Pharmacol 1998; 45: 123–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Batty KT, Le AT, Ilett KF, et al. A pharmacokinetic and pharmacodynamics study of artesunate for vivax malaria. Am J Trop Med Hyg 1998; 59: 823–7.PubMedGoogle Scholar
  25. 25.
    Newton P, Suputtamongkol Y, Teja-Isavadharm P, et al. Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrob Agents Chemother 2000; 44: 972–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Teja-Isavadharm P, Nosten F, Kyle DE, et al. Comparative bioavailability of rectal, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay. Br J Clin Pharmacol 1996; 42: 599–604.PubMedGoogle Scholar
  27. 27.
    Karbwang J, Na-Bangchang K, Congpuong K, et al. Pharmacokinetics and bioavailability of oral and intramuscular artemether. Eur J Clin Pharmacol 1997; 52: 307–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Murphy SA, Mberu E, Muhia D, et al. The disposition of intramuscular artemether in children with cerebral malaria: a preliminary study. Trans R Soc Trop Med Hyg 1997; 91(3): 331–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Niu X, Ho L, Ren Z, et al. Metabolic fate of qinghaosu in rats: a new tlc densitometric method for its determination in biological material. Eur J Drug Metab Pharmacokinet 1985; 10: 55–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhao KC, Song ZY. Distribution and excretion of artesunate in rats. Proc Chin Acad Med Sci Peking Union Med Coll 1989; 4(4): 186–8.PubMedGoogle Scholar
  31. 31.
    Jiang JR, Zou CD, Shu HL, et al. Assessment of absorption and distribution of artemether in rats using a thin layer chromatography scanning technique. Acta Pharmacol Sin 1989; 10(5): 431–4.Google Scholar
  32. 32.
    Noker PE, Simpson-Herren L. Absorption, bioavailability, tissue distribution, metabolic profile, elimination and pharmacokinetics of 14C-artelinic acid in rats. Birmingham (AL): Southern Research Institute, 1998 (Data on file).Google Scholar
  33. 33.
    Noker PE, Simpson-Herren L. Whole body autoradiography of 14C-artelinic acid in rats. Birmingham (AL): Southern Research Institute, 1998 (Data on file).Google Scholar
  34. 34.
    Edlund PO, Westerlund D, Carlqvist J, et al. Determination of artesunate and dihydroartemisinin in plasma by liquid chromatography with post-column derivatization and UV detection. Acta Pharm Sci 1984; 21: 223–34.Google Scholar
  35. 35.
    Li Q-G, Peggins JO, Fleckenstein L, et al. Binding characteristics of 14C-arteether, 14C-artemether, and 14C-dihydro-artemisinin to plasma proteins and red blood cells of human and animal species in vivo and in vitro. [abstract PpA 144]. 21st Annual Meeting of the Society for Experimental Biology; 1998; San Francisco.Google Scholar
  36. 36.
    Li QG, Peggins JO, Lin AJ, et al. Pharmacology and toxicology of artelinic acid: preclinical investigations on pharmacokinetics, metabolism, protein and red blood cell binding, and acute and anorectic toxicities. Trans R Soc Trop Med Hyg 1998; 92(3): 332–40.PubMedCrossRefGoogle Scholar
  37. 37.
    Bakhshi HB, Gordi T, Ashton M. In vitro interaction of artemisinin with intact human erythrocytes, erythrocyte ghosts, haemoglobin and carbonic anhydrase. J Pharm Pharmacol 1997: 49(2): 223–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Gu HM, Warhurst DC, Peters W. Uptake of [3H]dihydroartemisinin by erythrocytes infected with Plasmodium falciparum in vitro. Trans R Soc Trop Med Hyg 1984; 78(2): 265–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Asawamahasakda W, Benakis A, Meshnick SR. The interaction of artemisinin with red cell membranes. J Lab Clin Med 1994; 123(5): 757–62.PubMedGoogle Scholar
  40. 40.
    Edwards G, Ward S, Breckenridge A. Interaction of arteether with the red blood cell in vitro and its possible importance in the interpretation of plasma concentrations in vivo. J Pharm Pharmacol 1991; 44: 280–1.CrossRefGoogle Scholar
  41. 41.
    Li WH, Shu HL, Xu GY, et al. The binding of qinghaosu (artemisinine) and its derivatives to plasma protein [in Chinese]. Acta Pharmacol Sin 1982; 17: 783–6.Google Scholar
  42. 42.
    Wanwimolruk S, Edwards G, Ward SA, et al. The binding of the antimalarial arteether to human plasma proteins in vitro. J Pharm Pharmacol 1992; 44(11): 940–2.PubMedCrossRefGoogle Scholar
  43. 43.
    Mansor SM, Molyneux ME, Taylor TE, et al. Effect of Plasmodium falciparum malaria infection on the plasma concentration of alpha-acid glycoprotein and the binding of quinine in Malawian children. Br J Clin Pharmacol 1991; 32: 317–21.PubMedCrossRefGoogle Scholar
  44. 44.
    Colussi D, Parisot C, Legay F, et al. Binding of artemether and lumefantrine to plasma proteins and erythrocytes. Eur J Pharm Sci 1999; 9(1): 9–16.PubMedCrossRefGoogle Scholar
  45. 45.
    Yang YZ, Asawamahasakda W, Meshnick SR. Alkylation of human albumin by the antimalarial artemisinin. Biochem Pharmacol 1993; 46(2): 336–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Yang YZ, Little B, Meshnick SR. Alkylation of proteins by artemisinin: effects of heme, pH, and drug structure. Biochem Pharmacol 1994; 48(3): 569–73.PubMedCrossRefGoogle Scholar
  47. 47.
    Zhao S. High-performance liquid chromatography determination of artemisinin in human plasma and saliva. Analyst 1987; 112: 661–4.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhao S, Zeng M-Y. Application of precolumn reaction to high-performance liquid chromatography of qinghaosu in animal plasma. Anal Chem 1986; 58: 289–92.CrossRefGoogle Scholar
  49. 49.
    Muhia DK, Mberu EK, Watkins WM. Differential extraction of artemether and its metabolite dihydroartemisinin from plasma and determination by high-performance liquid chromatography. J Chromatogr A 1994; 660: 196–9.Google Scholar
  50. 50.
    Thomas CG, Ward SA. Selective determination, in plasma, of artemether and its major metabolite, dihydroartemisinin, by high performance liquid chromatography with ultraviolet detection. J Chromatogr A 1992; 583: 131–6.Google Scholar
  51. 51.
    Samdrenan B, Sioufi A, Godbillon J, et al. Determination artemether and its metabolite dihydroartemisinin in plasma by high-performance liquid chromatography and electrochemical detection in the reductive mode. J Chromatogr B Biomed Sci Appl 1987; 691(1): 145–53.CrossRefGoogle Scholar
  52. 52.
    Navaratnam V, Mansor SM, Chin LK, et al. Determination of artemether and dihydroartemisinin in blood plasma by high-performance liquid chromatography for application in clinical pharmacological studies. J Chromatogr B Biomed Appl 1995; 669(2): 289–94.PubMedCrossRefGoogle Scholar
  53. 53.
    Idowu OR, Edwards G, Ward SA, et al. Determination of arteether in blood plasma by high performance liquid chromatography with ultraviolet detection after hydrolyis acid. J Chromatogr A 1989; 493: 125–36.Google Scholar
  54. 54.
    Zhou ZM, Anders JC, Chung H, et al. Analysis of artesunic acid and dihydroqinghaosu in blood by high-performance liquid chromatography with reductive electrochemical detection. J Chromatogr A 1987; 414(1): 77–90.Google Scholar
  55. 55.
    Batty KT, Davis TM, Thu LT, et al. Selective high-performance liquid chromatographic determination of artesunate and alpha- and beta-dihydroartemisinin in patients with falciparum malaria. J Chromatogr B Biomed Appl 1996; 677(2): 345–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Navaratnam V, Mordi MN, Mansor SM. Simultaneous determination of artesunic acid and dihydroartemisinin in blood plasma by highperformance liquid chromatography for application in clinical pharmacological studies. J Chromatogr B Biomed Sci Appl 1997; 692(1): 157–62.PubMedCrossRefGoogle Scholar
  57. 57.
    Na-Bangchang K, Congpuong K, Hung LN, et al. Simple high-performance liquid chromatographic method with electrochemical detection of artesunate and dihydroartemisinin in biological fluids. J Chromatogr B Biomed Sci Appl 1998; 7081(2): 201–7.CrossRefGoogle Scholar
  58. 58.
    Theoharides AD, Smyth MH, Ashmore RW, et al. Determination of the dihydroqinghaosu by pyrolysis gas chromatography/mass spectrometry. Anal Chem 1988; 60: 115–20.PubMedCrossRefGoogle Scholar
  59. 59.
    Navaratnam V, Mordi MN, Mansor SM, et al. Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers. Br J Clin Pharmacol 1997; 43: 363–5.PubMedGoogle Scholar
  60. 60.
    Hassan Alin M, Ashton M, Kihamia CM, et al. Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 1996; 90(1): 61–5.PubMedCrossRefGoogle Scholar
  61. 61.
    Ashton M, Hai TN, Sy ND, et al. Artemisinin pharmacokinetics is time-dependent during repeated oral administration in healthy male adults. Drug Metab Dispos 1998; 26(1): 25–7.PubMedGoogle Scholar
  62. 62.
    Khanh NX, de Vries PJ, Ha LD, et al. Declining concentrations of dihydroartemisinin in plasma during 5-day oral treatment with artesunate for falciparum malaria. Antimicrob Agents Chemother 1999; 43(3): 690–2.PubMedGoogle Scholar
  63. 63.
    Karbwang J, Na-Bangchang K, Thanavibul A, et al. Plasma concentrations of artemether and its major plasma metabolite, dihydroartemisinin, following a 5-day regimen of oral artemether, in patients with uncomplicated falciparum malaria. Ann Trop Med Parasitol 1998; 92(1): 31–6.PubMedCrossRefGoogle Scholar
  64. 64.
    van Agtmael MA, Cheng-Qi S, Qing JX, et al. Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria. Int J Antimicrob Agents 1999; 12(2): 151–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Svensson USH, Sandstrom R, Carlborg O, et al. High in situ rat intestinal permeability of artemisinin unaffected by multiple dosing and with no evidence of P-glycoprotein involvement. Drug Metab Dispos 1999; 27(2): 227–32.PubMedGoogle Scholar
  66. 66.
    Augustijns P, D’Hulst A, van Daele J, et al. Transport of artemisinin and sodium artesunate in Caco-2 intestinal epithelial cells. J Pharm Sci 1996; 85(6): 577–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Titulaer HA, Zuidema J, Lugt CB. Formulation and pharmacokinetics of artemisinin and its derivatives. Int J Pharm 1991; 69: 83–92.CrossRefGoogle Scholar
  68. 68.
    Lee IK, Hufford CD. Metabolism of antimalarial sesquiterpene lactones. Pharmacol Ther 1990; 48: 345–55.PubMedCrossRefGoogle Scholar
  69. 69.
    Maggs JL, Bishop LP, Edwards G, et al. Biliary metabolites of beta-artemether in rats: biotransformations of an antimalarial endoperoxide. Drug Metab Dispos 2000; 28(2): 209–17.PubMedGoogle Scholar
  70. 70.
    Chi HT, Ramu K, Baker JK, et al. Identification of the in vivo metabolites of the antimalarial arteether by thermospray high-performance liquid chromatography/mass spectrometry. Biol Mass Spectrom 1991; 20: 609–28.PubMedCrossRefGoogle Scholar
  71. 71.
    Leskovac V, Theoharides AD. Hepatic metabolism of artemisinin drugs-I: drug metabolism in rat liver microsomes. Comp Biochem Physiol 1991; 99C: 383–90.Google Scholar
  72. 72.
    Zhu DY, Huang BS, Chen ZL, et al. Isolation and identification of the metabolite of artemisinine in human [in Chinese]. Acta Pharmacol Sin 1983; 4: 194–7.Google Scholar
  73. 73.
    Maggs JL, Batty KT, Ilett KF, et al. Isomerization in human urine of a glucuronide of the antimalarial endoperoxide drug dihydroartemisinin [abstract]. Proceedings of the British Pharmacological Society; 1998 Apr 22–24; Chester.Google Scholar
  74. 74.
    Yang SD, Ma JM, Sun JH, et al. A preliminary study on the urinary excretion of artesunate and its metabolites in man after a single intravenous injection [in Chinese]. Acta Pharmacol Sin 1987; 22: 401–4.Google Scholar
  75. 75.
    Taylor P. Anticholinesterase agents. In: Goodman LS, Gilman A, editors. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985: 110–5.Google Scholar
  76. 76.
    Meyer UA. Overview of enzymes of drug metabolism. J Pharmacokinet Biopharm 1996; 24(5): 449–59.PubMedGoogle Scholar
  77. 77.
    Ashton M, Johansson L, Thornqvist AS, et al. Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat. Xenobiotica 1999; 29(2): 195–204.PubMedCrossRefGoogle Scholar
  78. 78.
    Svensson US, Ashton M. Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br J Clin Pharmacol 1999; 48(4): 528–35.PubMedCrossRefGoogle Scholar
  79. 79.
    Grace JM, Aguilar AJ, Trotman KM, et al. Metabolism of β-arteether to dihydroqinghaosu by human liver microsomes and recombinant cytochrome P450. Drug Metab Dispos 1998; 26(4): 313–7.PubMedGoogle Scholar
  80. 80.
    van Agtmael MA, van der Graaf CA, Dien TK, et al. The contribution of the enzymes CYP2D6 and CYP2C19 in the demethylation of artemether in healthy subjects. Eur J Drug Metab Pharmacokinet 1998; 23(3): 429–36.PubMedCrossRefGoogle Scholar
  81. 81.
    Gonzalez FJ. The CYP2D subfamily. In: Ioannides C, editor. Cytochrome P450: metabolic and toxicological aspects. Boca Raton (FL): CRC Press, 1996: 183–210.Google Scholar
  82. 82.
    Richardson TH, Johnson EF. The CYP2C subfamily. In: Ioannides C, editor. Cytochrome P450: metabolic and toxicological aspects. Boca Raton (FL): CRC Press, 1996: 161–81.Google Scholar
  83. 83.
    van Agtmael MA, Gupta V, van der Wosten TH, et al. Grapefruit juice increases the bioavailability of artemether. Eur J Clin Pharmacol 1999; 55(5): 405–10.PubMedCrossRefGoogle Scholar
  84. 84.
    van Agtmael MA, Gupta V, van der Graaf, CA, et al. The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects. Clin Pharmacol Ther 1999; 66(4); 408–14.PubMedCrossRefGoogle Scholar
  85. 85.
    Leskovac V, Theoharides AD. Hepatic metabolism of artemisinin drugs: I. Drug metabolism in rat liver microsomes. Comp Biochem Physiol 1991; 99C: 383–90.Google Scholar
  86. 86.
    de Waziers I, Cugnenc PH, Yang CS, et al. Cytochrome P450 isoenzymes epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther 1990; 253(1): 387–94.PubMedGoogle Scholar
  87. 87.
    Kolars JC, Schmiedlin-Ren P, Schuetz JD, et al. Identification of rifampicin-inducible P450IIIA4 in human small bowel enterocytes. J Clin Invest 1992; 90(5): 1871–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Grace JM, Skanchy DJ, Aguilar AJ. Metabolism of artelinic acid to dihydroqinghaosu by human liver cytochrome P4503A. Xenobiotica 1999; 29(7): 703–17.PubMedCrossRefGoogle Scholar
  89. 89.
    Svensson USH, Ashton M, Hai TN, et al. Artemisinin induces omeprazole metabolism in human beings. Clin Pharmacol Ther 1998; 64: 160–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Leo KU, Grace JM, Li Q, et al. Effects of Plasmodium berghei infection on artemether metabolism and disposition. Pharmacology 1997; 54: 276–84.PubMedCrossRefGoogle Scholar
  91. 91.
    Kokwaro GO, Glazier AP, Ward SA, et al. Effect of malaria infection and endotoxin-induced fever on phenacetin O-deethylation by rat liver microsomes. Biochem Pharmacol 1993; 45(6): 1235–41.PubMedCrossRefGoogle Scholar
  92. 92.
    Alvares AP, Veng TH, Scheibel LW, et al. Impairment of hepatic cytochrome P450 dependent mono-oxygenase by malarial parasites Plasmodium berghei. Mol Biochem Parasitol 1984; 13: 277–82.PubMedCrossRefGoogle Scholar
  93. 93.
    Mansor SM, Edwards G, Roberts PJ, et al. The effect of malaria infection on paracetamol disposition in the rat. Biochem Pharmacol 1991; 41: 1707–11.PubMedCrossRefGoogle Scholar
  94. 94.
    Ismail S, Kokwaro GO, Back DJ, et al. Effect of malaria infection on the pharmacokinetics of paracetamol in rat. Xenobiotica 1994; 24: 527–33.PubMedCrossRefGoogle Scholar
  95. 95.
    Na-Bangchang K, Karbwang J, Thomas CG, et al. Pharmacokinetics of artemether after oral administration to healthy Thai males and patients with acute, uncomplicated falciparum malaria. Br J Clin Pharmacol 1994; 37: 249–53.PubMedCrossRefGoogle Scholar
  96. 96.
    Karbwang J, Na-Bangchang K, Tin T, et al. Pharmacokinetics of intramuscular artemether in patients with severe falciparum malaria with or without acute renal failure. Br J Clin Pharmacol 1998; 45: 597–600.PubMedCrossRefGoogle Scholar
  97. 97.
    Duc DD, de Vries PJ, Nguyen XK, et al. The pharmacokinetics of a single dose of artemisinin in healthy Vietnamese subjects. Am J Trop Med Hyg 1994; 51(6): 785–90.PubMedGoogle Scholar
  98. 98.
    de Vries PJ, Nguyen XK, Tran KD, et al. The pharmacokinetics of a single dose of artemisinin in subjects with liver cirrhosis: Bach Mai-Amsterdam Research Group on Artemisinin. Trop Med Int Health 1997; 2(10): 957–62.PubMedCrossRefGoogle Scholar
  99. 99.
    Dien TK, de Vries PJ, Khanh NX, et al. Effect of food intake on the pharmacokinetics of oral artemisinin in healthy Vietnamese subjects. Antimicrob Agents Chemother 1997; 41(5): 1069–72.PubMedGoogle Scholar
  100. 100.
    White NJ, Olliaro PL. Strategies for the prevention of antimalarial drug resistance: rationale for combination chemotherapy for malaria. Parasitol Today 1996; 12(10): 399–401.PubMedCrossRefGoogle Scholar
  101. 101.
    Bunnag D, Viravan C, Looareesuwan S, et al. Clinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand: a preliminary report. Southeast Asian J Trop Med Pub Health 1991; 22: 380–5.Google Scholar
  102. 102.
    Looareesuwan S, Viravan C, Vanijanonta S, et al. Randomized trial of mefloquine-doxycycline, and artesunate-doxycycline for treatment of acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1994; 50(6): 784–9.PubMedGoogle Scholar
  103. 103.
    Duarte EC, Fontes CJ, Gyorkos TW, et al. Randomized controlled trial of artesunate plus tetracycline versus standard treatment (quinine plus tetracycline) for uncomplicated Plasmodium falciparum malaria in Brazil. Am J Trop Med Hyg 1996; 54(2): 197–202.PubMedGoogle Scholar
  104. 104.
    Na-Bangchang K, Tippanangkosol P, Ubalee R, et al. Comparative clinical trial of four regimens of dihydroartemisinin-mefloquine in multidrug-resistant falciparum malaria. Trop Med Int Health 1999; 4(9): 602–10.PubMedCrossRefGoogle Scholar
  105. 105.
    Na-Bangchang K, Karbwang J, Molunto P, et al. Pharmacokinetics of mefloquine, when given alone and in combination with artemether, in patients with uncomplicated falciparum malaria. Fundam Clin Pharmacol 1995; 9(6): 576–82.PubMedCrossRefGoogle Scholar
  106. 106.
    Alin MH, Ashton M, Kihamia CM, et al. Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria. Br J Clin Pharmacol 1996; 41(6): 587–92.PubMedCrossRefGoogle Scholar
  107. 107.
    Ducharme J, Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine: focus on recent advancements. Clin Pharmacokinet 1996; 31(4): 257–74.PubMedCrossRefGoogle Scholar
  108. 108.
    Halliday RC, Jones BC, Smith DA, et al. An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems. Br J Clin Pharmacol 1995; 40(4): 369–78.PubMedCrossRefGoogle Scholar
  109. 109.
    Baune B, Flinois JP, Furlan V, et al. Halofantrine metabolism in microsomes in man: major role of CYP3A4 and CYP3A5. J Pharm Pharmacol 1999; 51(4): 419–26.PubMedCrossRefGoogle Scholar
  110. 110.
    Zhao XJ, Ishizaki T. The in vitro hepatic metabolism of quinine in mice, rats and dogs: comparison with human liver microsomes. J Pharmacol Exp Ther 1997; 283(3): 1168–76.PubMedGoogle Scholar
  111. 111.
    Lin JH, Lu AYH. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol Rev 1997; 49(4): 403–49.PubMedGoogle Scholar
  112. 112.
    Na-Bangchang K, Karbwang J, Back DJ. Primaquine metabolism by human liver microsomes: effect of other antimalarial drugs. Biochem Pharmacol 1992; 44(3): 587–90.CrossRefGoogle Scholar
  113. 113.
    Na-Bangchang K, Karbwang J, Back DJ. Mefloquine metabolism by human liver microsomes: effect of other antimalarial drugs. Biochem Pharmacol 1992; 43(9): 1957–61.CrossRefGoogle Scholar
  114. 114.
    van Vugt M, Edstein MD, Proux S, et al. Absence of an interaction between artesunate and atovaquone-proguanil. Eur J Clin Pharmacol 1999; 55: 469–74.PubMedCrossRefGoogle Scholar
  115. 115.
    Tan-ariya P, Na-Bangchang K, Ubalee R, et al. Pharmacokinetic interactions of artemether and pyrimethamine in healthy male Thais. Southeast Asian J Trop Med Public Health 1998; 29(1): 18–23.PubMedGoogle Scholar
  116. 116.
    Na-Bangchang K, Tippawangkosol P, Thanavibul A, et al. Pharmacokinetic and pharmacodynamics interactions of mefloquine and dihydroartemisinin. Int J Clin Pharmacol Res 1999; 19(1): 9–17.PubMedGoogle Scholar
  117. 117.
    Lefevre G, Bindschedler M, Ezzet F, et al. Pharmacokinetic interaction trial between co-artemether and mefloquine. Eur J Pharm Sci 2000; 10(2): 141–51.PubMedCrossRefGoogle Scholar
  118. 118.
    Zhao KC, Song ZY. Pharmacokinetics of dihydroqinghaosu in human volunteers and comparison with qinghaosu [in Chinese]. Acta Pharmacol Sin 1993; 28(5): 342–6.Google Scholar
  119. 119.
    Hien TT, White NJ. Qinghaosu. Lancet 1993; 341: 603–8.PubMedCrossRefGoogle Scholar
  120. 120.
    Kamchonwongpaisan S, Vanitchareon N, Yuthavong Y. The mechanism of antimalarial action of artemisinin (Qinghaosu). In: Ong A, Sa H, Packer L, editors. Lipid-soluble antioxidants: biochemistry and clinical applications. Basel: Birkhauser-Verlag, 1992: 363–72.CrossRefGoogle Scholar
  121. 121.
    Kamchonwongpaisan S, Meshnick SR. The mode of action of the antimalarial artemisinin and its derivatives. Gen Pharmacol 1996; 27(4): 587–92.PubMedCrossRefGoogle Scholar
  122. 122.
    Robert A, Meunier B. Is alkylation the main mechanism of action of the antimalarial drug artemisinin?. Chem Soc Rev 1998; 27: 273–9.CrossRefGoogle Scholar
  123. 123.
    Haynes RK, Hung-On Pai H, Voerste A. Ring opening of artemisinin (Qinghaosu) and dihydroartemisinin and interception of the open hydroperoxides with formation of N-oxides: a chemical model for antimalarial mode of action. Tetrahedon Lett 1999; 40: 4715–8.CrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Visweswaran Navaratnam
    • 1
  • Sharif Mahsufi Mansor
    • 1
  • Nam-Weng Sit
    • 1
  • James Grace
    • 2
  • Qigui Li
    • 2
  • Piero Olliaro
    • 3
  1. 1.Centre for Drug ResearchUniversity Sains MalaysiaPenangMalaysia
  2. 2.Walter Reed Army Institute of ResearchUSA
  3. 3.UNDP/World Bank/WHO Special Programme for Research and Training in Tropical DiseasesCDS Cluster, World Health OrganizationGenevaSwitzerland

Personalised recommendations