Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics of the Diastereomers of Arteether in Healthy Volunteers

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Objective

To evaluate the pharmacokinetics of α- and β-diastereomers of arteether in healthy male volunteers.

Participants and methods

The study was a single-centre clinical pharmacokinetic trial in healthy male subjects. A group comprising 13 subjects aged 25–50 years received a single intramuscular 150mg individual dose of the arteether formulation containing α- and β-isomers in a 30: 70 ratio. Serial blood samples collected over a period of 0–192 hours were analysed by high-performance liquid chromatography-electrospray ionisation/tandem mass spectrometry and the plasma concentrations were subjected to compartmental and noncompartmental analyses. Pharmacodynamic parameters such as area under the inhibitory curve, ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC), maximum plasma concentration to MIC (Cmax/MIC) and time that plasma concentration exceeds the MIC (T>MIC) were calculated in vitro in four strains of Plasmodium falciparum to evaluate the in vivo effectiveness of the proposed dosage regimen.

Results

There were no adverse effects observed during the study. The extent of metabolism of arteether to dihydroartemisinin (DHA) was low (∼5%) so as to be therapeutically nonsignificant. The pharmacokinetic profiles of the arteether diastereomers were different, and the maximum plasma concentrations of α- and β-isomers were reached at 4.77 ± 1.21 hours and 6.96 ± 1.62 hours, respectively, after which they showed biphasic decline with apparent terminal elimination half-lives of 13.24 ± 1.08 hours and 30.17 ± 2.44 hours, respectively. The plasma and renal clearances, as well as whole blood to plasma partition ratios of the isomers, were comparable, while the apparent volume of distribution during terminal phase of the β-isomer was approximately 3-fold higher than that of the α-isomer. In vitro erythrocyte culture experiments with four strains of P. falciparum showed similar MICs for both isomers of arteether. The highest observed MIC of 8 µg/L was selected for estimating the pharmacokinetic and pharmacodynamic parameters, which showed excellent correlation with published data on the clinical efficacy of arteether.

Conclusion

The pharmacokinetics of arteether isomers demonstrated stereoselectivity, which was reflected mainly in the volume of distribution and the terminal elimination half-life. The α- and β-isomers of arteether appeared to compliment each other pharmacokinetically, with the α-isomer providing comparatively rapid and higher plasma concentrations resulting in immediate reduction in percentage parasitaemia, while the β-isomer, with its longer terminal elimination half-life, mean residence time and sustained plasma concentrations, maintained the activity for longer periods. The extent of metabolic conversion of arteether to DHA was minimal, so as to have any therapeutic or toxic significance.

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

Fig. 1
Table I
Table II
Table III
Fig. 2
Table IV
Table V
Table VI
Table VII

Similar content being viewed by others

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Cheng F, Shen J, Luo X, et al. Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues. Bioorg Med Chem 2002; 10: 2883–91

    Article  PubMed  CAS  Google Scholar 

  2. Price R, van Vugt M, Phaipun L, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 1999; 60: 547–55

    PubMed  CAS  Google Scholar 

  3. Shuhua X, Yuanqing Y, Qiqing Y, et al. Potential long-term toxicity of repeated orally administered doses of artemether in rats. Am J Trop Med Hyg 2002; 66: 30–4

    Google Scholar 

  4. Davidson DE. Role of arteether in the treatment of malaria and plans for further development. Trans R Soc Trop Med Hyg 1994; 88 Suppl. 1: 51–2

    Article  Google Scholar 

  5. Ahton M, Gordi T, Hai TN, et al. Artemisinin pharmacokinetics in healthy adults after 250, 500, and 1000mg single oral doses. Biopharm Drug Dispos 1998; 19: 245–50

    Article  Google Scholar 

  6. Li Q-G, Peggins JO, Fleckenstein LL, et al. The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats. J Pharm Pharmacol 1998; 50: 173–82

    Article  PubMed  CAS  Google Scholar 

  7. Tran TH, Day NP, Nguyen HP, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996; 335: 69–75

    Article  Google Scholar 

  8. 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: 151–8

    Article  PubMed  Google Scholar 

  9. Tripathi R, Dutta GP, Vishwakarma RA. Comparison of antimalarial efficacy of a, β and α/β-arteether against Plasmodium cyanomolgi B infection in monkeys. Am J Trop Med Hyg 1991; 44: 560–3

    PubMed  CAS  Google Scholar 

  10. Brossi A, Venugopalan B, Dominguez Gerpe L, et al. Arteether, a new antimalarial drug: synthesis and antimalarial properties. J Med Chem 1988; 31: 645–50

    Article  PubMed  CAS  Google Scholar 

  11. Singh C, Tiwari P. A one pot conversion of artemisinin to its ether derivatives. Tetrahedron Lett 2002; 43: 7235–7

    Article  CAS  Google Scholar 

  12. Tripathi R, Vishwakarma RA, Dutta GP. Plasmodium fragile: efficacy of arteether (α/β) against cerebral malaria model. Exp Parasitol 1997; 87: 290–2

    Article  PubMed  CAS  Google Scholar 

  13. World Health Organisation (WHO). Review of application for inclusion of a drug in the WHO essential drugs list. CDS/RBM. Geneva: WHO, 2002

    Google Scholar 

  14. Asthana OP, Srivastava JS, Kamboj VP, et al. A multicentric study with arteether in patients of uncomplicated falciparum malaria. J Assoc Physicians India 2001; 49: 692–6

    PubMed  CAS  Google Scholar 

  15. Brocks DR, Mehvar R. Stereoselectivity in the pharmacodynamics and pharmacokinetics of the chiral antimalarial drugs. Clin Pharmacokinet 2003; 42: 1359–82

    Article  PubMed  CAS  Google Scholar 

  16. Isavadharm PJ, Nosten F, Kyle DE, et al. Comparative bioavailability of oral, 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

    Google Scholar 

  17. Batty KT, Ilett KF, Powel SM, et al. Relative bioavailability of artesunate and dihydroartemisinin: investigations in the isolated perfused rat liver and in healthy Caucasian volunteers. Am J Trop Med Hyg 2002; 66(2): 130–6

    PubMed  CAS  Google Scholar 

  18. Svensson USH, Sandstorm 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 1998; 27: 227–32

    Google Scholar 

  19. Karbwang J, Na-Bangchang K, Congpoung K, et al. Pharmacokinetics of oral artesunate in Thai patients with uncomplicated falciparum malaria. Clin Drug Invest 1998; 45: 597–600

    CAS  Google Scholar 

  20. Singh N, Shukla MM, Asthana OP, et al. Effectiveness of α/β-arteether in clearing Plasmodium falciparum parasitemia in central India. Southeast Asian J Trop Med Public Health 1998; 29: 225–7

    PubMed  CAS  Google Scholar 

  21. Mishra SK, Asthana OP, Mohanty S, et al. Effectiveness of α/β-arteether in acute falciparum malaria. Trans R Soc Trop Med Hyg 1995; 89: 299–301

    Article  PubMed  CAS  Google Scholar 

  22. Kager PA, Schultz MJ, Zijlstra EE, et al. Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance. Trans R Soc Trop Med Hyg 1994; 88 Suppl. 1: 53–4

    Article  Google Scholar 

  23. Hufford CD, Lee IS, ElSohly HN, et al. Structure elucidation and thermospray high performance liquid chromatography/mass spectroscopy of the microbial and mammalian metabolites of the antimalarial arteether. Pharm Res 1990; 7(9): 923–7

    Article  PubMed  CAS  Google Scholar 

  24. Maggs JL, Bishop LPD, Edwards G, et al. Biliary metabolites of β-artemether in rats: biotransformations of an antimalarial endoperoxide. Drug Metab Dispos 1999; 28(2): 209–16

    Google Scholar 

  25. Ramu K, Baker JK. Identification of the glucuronides of the hydroxylated metabolites of the antimalarial arteether in rat plasma and urine by thermospray high performance liquid chromatography/mass spectrometry. J Pharm Sci 1997; 86(8): 915–27

    Article  PubMed  CAS  Google Scholar 

  26. Navaratnam V, Mansor SM, Sit N-W, et al. Pharmacokinetics of artemisinin type compounds. Clin Pharmacokinet 2000; 39(4): 255–70

    Article  PubMed  CAS  Google Scholar 

  27. Grace JM, Aguilar AJ, Trotman KM, et al. Metabolism of β-arteether to dihydroartemisinin by human liver microsomes and recombinant cytochrome P450. Drug Metab Dispos 1997; 26(4): 313–7

    Google Scholar 

  28. Sabarinath S, Rajanikanth M, Madhusudanan KP, et al. A sensitive and selective liquid chromatographic/electrospray ionization tandem mass spectrometric assay for the simultaneous quantification of α-, β-arteether and its metabolite dihydroartemisinin in plasma, useful for pharmacokinetic studies. J Mass Spectrom 2003; 38: 732–42

    Article  PubMed  CAS  Google Scholar 

  29. Shah VP, Midha KK, Findlay JW, et al. Bioanalytical method validation: a revisit with a decade of progress. Pharm Res 2000; 17: 1551–9

    Article  PubMed  CAS  Google Scholar 

  30. Rieckmann KH, Sax LJ, Campbell GH, et al. Drug sensitivity of P. falciparum, an in vitro microtechnique. Lancet 1978; I: 22–3

    Article  Google Scholar 

  31. Okoyeh JN, Pillai CR, Chitnis CE. Plasmodium falciparum field isolates commonly use erythrocyte invasion pathways that are independent of sialic acid residues of glycoprotein A. Infect Immun 1999; 67: 5784–91

    PubMed  CAS  Google Scholar 

  32. Lambros C, Vanderberg JP. Synchronisation of P. falciparum erythrocytic stage in culture. J Parasitol 1979; 65: 418–21

    Article  PubMed  CAS  Google Scholar 

  33. Mouton JW, Dudley MN, Cars O, et al. Standardization of pharmacokinetic/pharmacodynamics (PK/PD) terminology for anti-infective drugs. Int J Antimicrob Agents 2002; 19: 355–8

    Article  PubMed  CAS  Google Scholar 

  34. Ludden TM, Beal SL, Sheiner LB. Comparison of Akaike Information Criterion, the Schwar Criterion and the F-test as guides to model selection. J Pharmacokinet Biopharm 1994; 22(5): 431–45

    PubMed  CAS  Google Scholar 

  35. Basco LK, Le Bras J. In vitro activity of artemisinin derivatives against African isolates and clones of Plasmodium falciparum. Am J Trop Med Hyg 1993; 49(3): 301–7

    PubMed  CAS  Google Scholar 

  36. Wu Y. How might Qinghaosu and related compounds kill the intraerythrocytic malaria parasite? A chemist’s view. Acc Chem Res 2002; 35(5): 255–9

    Article  PubMed  CAS  Google Scholar 

  37. Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 2002; 32: 1655–60

    Article  PubMed  CAS  Google Scholar 

  38. Olliaro PL, Haynes RK, Meunier B, et al. Possible modes of action of the artemisinin type compounds. Trends Parasitol 2001; 17: 122–6

    Article  PubMed  CAS  Google Scholar 

  39. Ludwig UE, Webb RJ, van Gothem IDA, et al. Artemisinins target SERCA of Plasmodium falciparum. Nature 2003; 424: 957–61

    Article  Google Scholar 

  40. Gibaldi M, Perrier D. Pharmacokinetics. 2nd rev. ed. New York: Marcel Dekker Inc., 1982

    Google Scholar 

  41. Puri SK, Srivastava K. In vitro evaluation of artemisinin derivatives in plasmodium strains. Lucknow: Parasitology Division, Central Drug Research Institute, 2004. (Data on file)

    Google Scholar 

  42. Li QG, Mog SR, Si YZ, et al. Neurotoxicity and efficacy of arteether related to its exposure times and levels in rodents. Am J Trop Med Hyg 2002; 66(5): 516–25

    PubMed  CAS  Google Scholar 

  43. Brewer TG, Grate SJ, Peggins JO, et al. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 1994; 51(3): 251–9

    PubMed  CAS  Google Scholar 

  44. Toutain PL, del Castillo JRE, Bousquet-Melou A. The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics. Res Vet Sci 2002; 73: 105–14

    Article  PubMed  CAS  Google Scholar 

  45. AliAbadi FS, Lees P. Antibiotic treatment for animals: effect on bacterial population and dosage regimen optimization. Int J Antimicrob Agents 2000; 14: 307–13

    Article  PubMed  CAS  Google Scholar 

  46. Dutta GP, Bajpai R, Vishwakarma RA. Comparison of antimalarial efficacy of artemisinin (Qinghaosu) and arteether against Plasmodium cyanomolgi B infection in monkeys. Trans R Soc Trop Med Hyg 1989; 83: 56–67

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dr C.M. Gupta, Director, Central Drug Research Institute, India, for providing the facilities for conducting this study. We are thankful to the Department of Science and Technology (DST) and Council of Scientific and Industrial Research (CSIR), India, for financial assistance. We would like to express our sincere gratitude to Dr Chandan Singh, Medicinal Chemistry Division, for providing propyl ether analogue of β-arteether and thank Ms Deepali Rathore of the Pharmacokinetics and Metabolism Division, and Mr J.R. Gupta of the Clinical and Experimental Medicine Division, for their excellent technical assistance. The authors have no conflicts of interest directly relevant to the contents of this study.

Author information

Authors and Affiliations

  1. Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Post Box No. 173, Chattar Manzil Palace, Mahatma Gandhi Marg, Lucknow, 226001, India

    Sreedharan N. Sabarinath &  Ram C. Gupta

  2. Clinical and Experimental Medicine Division, Central Drug Research Institute, Lucknow, India

    Omkar P. Asthana

  3. Parasitology Division, Central Drug Research Institute, Lucknow, India

    Sunil K. Puri & Kumkum Srivastava

  4. Sophisticated Analytical Instrumentation Facility, Central Drug Research Institute, Lucknow, India

    Kunnath P. Madhusudanan

Authors
  1. Sreedharan N. Sabarinath
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Omkar P. Asthana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sunil K. Puri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kumkum Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kunnath P. Madhusudanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ram C. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ram C. Gupta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabarinath, S.N., Asthana, O.P., Puri, S.K. et al. Clinical Pharmacokinetics of the Diastereomers of Arteether in Healthy Volunteers. Clin Pharmacokinet 44, 1191–1203 (2005). https://doi.org/10.2165/00003088-200544110-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200544110-00006

Keywords

Search

Navigation