Skip to main content

Advertisement

SpringerLink
Log in

Bioavailability and Pharmacokinetics of Dihydroartemisinin (DHA) and its Analogs—Mechanistic Studies on its ADME

  • Molecular Drug Disposition (H Sun, Section Editor)
  • Published:
Current Pharmacology Reports Aims and scope Submit manuscript

Abstract

Malaria is an infectious disease that continues to be linked with considerable morbidity and mortality, and significant social and economic impact in developing countries Malaria is transmitted from person to person by the bite of mosquitoes infected with the protozoan parasite Plasmodium spp. P. falciparum, P. vivax, P. malariae, and P. ovale. Of these, P. falciparum is responsible for over 90% of cases and almost all of the malaria deaths worldwide. This review discusses the epidemiology of malaria, its transmission and clinical manifestations, and the current malaria treatment regimens with emphasis on the artemisinins. Included are the efficacy of the artemisinins and their mechanism of action. Their low bioavailability was linked to extensive metabolism, as well as their chemical instability. Different factors that have permitted the emerging resistance to the artemisinins were showcased, probably as poor-dosing regimen and substandard products in developing countries. Also discussed were the plasmodial genes so far implicated in artemisinin resistance. Lastly, based on the available evidence with regard to bioavailability, metabolism, stability, drug transport, and pharmacokinetics, different approaches were proffered for formulations that will enhance therapeutics efficacy.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Acker KV, Mommaerts M, Vanermen S, Meskens J, Heyden YV, Vercammen J-P. Chemical stability of artemisinin derivatives. Malar J. 2012;11(1):99.

    Article  Google Scholar 

  2. Akuodor GC, Ajoku GA, Ezeunala MN, Chilaka KC, Asika EC. Antimalarial potential of the ethanolic leaf extract of Pseudocedrala kotschy. J Acute Dis. 2015:23–7.

  3. Anderson TJ, Nair S, Qin H, Singlam S, Brockman A, Paiphun L, et al. Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance? Antimicrob Agents Chemother. 2005;49(6):2180–8. https://doi.org/10.1128/AAC.49.6.2180-2188.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Anderson TJ, Nair S, Nkhoma S, Williams JT, Imwong M, Yi P, et al. High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. J Infect Dis. 2010;201(9):1326–30. https://doi.org/10.1086/651562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Andrade BB, Reis-Filho A, Souza-Neto SM, Clarencio J, Camargo LM, Barral A, et al. Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance. Malar J. 2010;9:1–13.

    Article  Google Scholar 

  6. Ansari MT, Saify ZS, Sultana N, Ahmad I, Saeed-Ul-Hassan S, Tariq I, et al. Malaria and artemisinin derivatives: an updated review. Mini-Rev Med Chem. 2012;13(13):1879–902. https://doi.org/10.2174/13895575113136660097.

    Article  Google Scholar 

  7. Ansari MT, Ahmad I, Hassan SSU, Tariq I, Murtaza G. Solubility enhancement of dihydroartemisinin using mixture of hydroxypropyl-cyclodextrin and PEG-6000. Lat Am J Pharm. 2014;33(3):483–91.

    CAS  Google Scholar 

  8. Ariey F, Witkowski B, Amaratunga BJ, Langlois AC, Khim N, Kim S, et al. Molecular marker of artemisinin-resistant P. falciparum malaria. Nature. 2014;505(7481):50–5. https://doi.org/10.1038/nature12876.

    Article  PubMed  Google Scholar 

  9. Arora DR, Arora B. Medical parasitology. 2nd ed. India: CBS Publishers & Distributors; 2009. p. 67–81.

    Google Scholar 

  10. Ashley EA, Dhorda ML, Fairhurst RM, Amaratunga C, Lim P, SSS S, et al. Spread of artemisinin resistance in P. falciparum malaria. N Engl J Med. 2014;371(5):411–23. https://doi.org/10.1056/NEJMoa1314981.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ashutosh S, Sajeev C, Jayaram B, Indira G. A plausible mechanism for the antimalarial activity of artemisinin: a computational approach. Sci Rep. 2013;3:2513.

    Article  Google Scholar 

  12. Augustijns P, D’hulst A, van Daele J, Kinget R. Transport of artemisinin and sodium artesunate in Caco-2 intestinal epithelial cells. J Pharm Sci. 1996;85(6):577–9. https://doi.org/10.1021/js960001i.

    Article  CAS  PubMed  Google Scholar 

  13. Balogun EA, Adebayo JO, Zailani AH, Kolawole OM, Ademowo OG. Activity of ethanolic extract of Clerodendrum violaceum leaves against. Plasmodium berghei in mice. Agric Biol J N Am. 2009;1(3):307–12.

    Article  Google Scholar 

  14. Barnes KI, Watkins WM, White NJ. Antimalarial dosing regimens and drug resistance—a review. Cell. 2008;24(3:127–34.

    Google Scholar 

  15. Bayoh MN, Lindsa SW. Temperature-related duration of aquatic stages of the Afrotropical malaria vector mosquito Anopheles gambiae in the laboratory. Med Vet Entomol. 2004;18(2):174–9. https://doi.org/10.1111/j.0269-283X.2004.00495.x.

    Article  CAS  PubMed  Google Scholar 

  16. Benjamin JV, Rosanne WW, Danielle K, Ingeborg MN, Sabine B, Michèle, et al. Efficacy and safety of artemisinin combination therapy (ACT) for non- falciparum malaria: a systematic review. Malar J. 2014;13:463.

    Article  Google Scholar 

  17. Bhisutthibhan J, Pan XQ, Hossler PA, Walker DJ, Yowell CA, Carlton J, et al. The P. falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. J Biol Chem. 1998;273(26):16192–8. https://doi.org/10.1074/jbc.273.26.16192.

    Article  CAS  PubMed  Google Scholar 

  18. Briggs H. Call for ‘radical action’ on drug-resistant malaria BBC News, health. 2014. Retrieved 30 July 2013.

  19. Centers for Disease Control (CDC). 2017a. Retrieved on March 16, 2017 from https://www.cdc.gov/malaria/about/biology/parasites.html.

  20. Centers for Disease Control (CDC). Malaria: where malaria occurs. 2017b. Retrieved on March 31, 2017 from https://www.cdc.gov/malaria/about/distribution.html.

  21. Cheesbrough M. District laboratory practice in tropical countries. New York-Cambridge press. 2006;1(2):249–258.

  22. Cheeseman IH, Miller BA, Nair S, Nkhoma S, Tan A, Tan JC, et al. A major genome region underlying artemisinin resistance in malaria. Science. 2012;336(6077):79–82. https://doi.org/10.1126/science.1215966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chemspider. Dihydroartemisinin. 2017. Retrieved on 1–22-2017 from http://www.chemspider.com/Chemical-Structure.2272104.html.

  24. Chen J, Lin H, Hu M. Metabolism of flavonoids via enteric recycling: role of intestinal disposition. J Pharmacol Exp Ther. 2003;304(3):1228–35. https://doi.org/10.1124/jpet.102.046409.

    Article  CAS  PubMed  Google Scholar 

  25. Craig MH, Snow RW, le Sueur D. A climate-based distribution model of malaria transmission in sub-Saharan Africa. Parasitol Today. 1999;15(3):105–10. https://doi.org/10.1016/S0169-4758(99)01396-4.

    Article  CAS  PubMed  Google Scholar 

  26. Croft A. Malaria: prevention in travelers. BMJ. 2010;15:154–60.

    Google Scholar 

  27. Crowe A, Ilett KF, Karunajeewa HA, Batty KT, Davis TME. Role of P glycoprotein in absorption of novel antimalarial drugs. Antimicrob Agents Chemother. 2006;50(10):3504–6. https://doi.org/10.1128/AAC.00708-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cui L, Wang Z, Miao J, Miao M, Chandra R, Jiang H, et al. Mechanism of in vitro resistance to dihydroartemisinin in P. falciparum. Mol Microbiol. 2012;86(1):111–28. https://doi.org/10.1111/j.1365-2958.2012.08180.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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. https://doi.org/10.2165/00003495-199652060-00004.

    Article  PubMed  Google Scholar 

  30. Dondorp AM, Fairhurst RM, Slutsker L, Macarthur JR, Breman JG, Guerin PJ, Wellems TE., Ringwald P, Newman RD., Plowe CV. The threat of artemisinin-resistant malaria. N Engl J Med. 2011;365(12):1073–5.

  31. Dwivedi P, Khatika R, Khandelwal K, Taneja I, Wahajuddin RKS, Paliwal SK, et al. Pharmacokinetics study of arteether loaded solid lipid nanoparticles: an improved oral bioavailability in rats. Int J Pharm. 2014;466(1–2):321–7. https://doi.org/10.1016/j.ijpharm.2014.03.036.

    Article  CAS  PubMed  Google Scholar 

  32. Enserink M. Malaria’s drug miracle in danger. Science. 2010;328(5980):844–6. https://doi.org/10.1126/science.328.5980.844.

    Article  CAS  PubMed  Google Scholar 

  33. Fujioka Y, Metsugi Y, Ogawara K, Higaki K, Kimura T. Evaluation of in-vivo dissolution behavior and GI transit of griseofulvin, a BCS class II drug. Int J Pharm. 2008;352(1-2):36–43. https://doi.org/10.1016/j.ijpharm.2007.10.008.

    Article  CAS  PubMed  Google Scholar 

  34. Ge S, Taijun Y, Xu B, Gao S, Hu M. Curcumin affects phase II disposition of resveratrol through inhibiting efflux transporters MRP2 and BCRP. Pharm Res. 2016;33(3):590–602.

    Article  CAS  PubMed  Google Scholar 

  35. Hall Z, Allan EL, van Schalkwyk DA, van Wyk A, Kaur H. Degradation of artemisinin-based combination therapies under tropical conditions. Am J Trop Med Hyg. 2016;94(5):993–1001. https://doi.org/10.4269/ajtmh.15-0665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Haynes RK, Ho-Ning W, Ho-Wai C, Shek LY, Chung-Man L, Williams ID, et al. Artesunate and dihydroartemisinin (DHA): unusual decomposition products formed under mild conditions and comments on the fitness of DHA as an antimalarial drug. Chem Med Chem. 2007;2(10):1448–63. https://doi.org/10.1002/cmdc.200700064.

    Article  CAS  PubMed  Google Scholar 

  37. Haynes RK, Cheu KW, Li KY, Tang MMK, Wong HN, Chen MJ, et al. A partial convergence in action of methylene blue and artemisinins: antagonism with chloroquine, a reversal with verapamil, and an insight into the antimalarial activity of chloroquine. Chem Med Chem. 2011;6(9):1603–15. https://doi.org/10.1002/cmdc.201100184.

    Article  CAS  PubMed  Google Scholar 

  38. Hien TT, Hanpithakpong W, Truong NT, Dung NT, Toi PV, Farrar J, et al. Orally formulated artemisinin in healthy fasting Vietnamese male subjects: a randomized, four-sequence, open-label, pharmacokinetic crossover study. Clin Ther. 2011;33(5):644–54. https://doi.org/10.1016/j.clinthera.2011.04.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hong X, Liu CH, Huang XT, Huang TL, Ye SM, Ou WP, et al. Pharmacokinetics of dihydroartemisinin in artekin tablets for single and repeated dosing in Chinese healthy volunteers. Pharmacokinetics of dihydroartemisinin in Artekin tablets for single and repeated dosing in Chinese healthy volunteers. Biopharm Drug Dispos. 2008;29(4):237–44. https://doi.org/10.1002/bdd.607.

    Article  CAS  PubMed  Google Scholar 

  40. Htut ZW. Artemisinin resistance in P.falciparum malaria. N Engl J Med. 2009;361(18):1807–8.

    Article  CAS  PubMed  Google Scholar 

  41. Huang H, Lu W, Li X, Cong X, Ma H, Liu X, et al. Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent. Bioorg Med Chem Lett. 2012;22(2):958–62. https://doi.org/10.1016/j.bmcl.2011.12.011.

    Article  CAS  PubMed  Google Scholar 

  42. Hunt P, Afonso A, Creasey A, Culleton R, Sidhu AB, Logan J, et al. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites. Mol Microbiol. 2007;65(1):27–40. https://doi.org/10.1111/j.1365-2958.2007.05753.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ilett KF, Batty KT, Powell SM, Binh TTLTA, Phuong HL, Hung NC, et al. The pharmacokinetic properties of intramuscular artesunate and rectal dihydroartemisinin in uncomplicated falciparum malaria. Br J Clin Pharmacol. 2002a;53(1):23–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, et al. Glucuronidation of dihydroartemisinin in vivo and by human livermicrosomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2002b;30(9):1005–12. https://doi.org/10.1124/dmd.30.9.1005.

    Article  CAS  PubMed  Google Scholar 

  45. Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, et al. Antimalarial drugs: modes of action and mechanisms of parasite resistance. Future Microbiol. 2010;5(12):1857–73.

    Article  Google Scholar 

  46. Imada C, Takahashi T, Kuramoto M, Masuda K, Ogawara K, Sato A, et al. Improvement of oral bioavailability of N-251, a novel antimalarial drug, by increasing lymphatic transport with long-chain fatty acid-based self- nanoemulsifying drug delivery system. Pharm Res. 2015;32(8):2595–608. https://doi.org/10.1007/s11095-015-1646-x.

    CAS  PubMed  Google Scholar 

  47. Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, et al. Resistance of Plasmodium falciparum field isolates to in vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet. 2005;366(9501):1960–3. https://doi.org/10.1016/S0140-6736(05)67787-2.

    Article  CAS  PubMed  Google Scholar 

  48. Jones MK, Good MF. Malaria parasites up close. Nat Med. 2006;12(2):170–1. https://doi.org/10.1038/nm0206-170.

    Article  CAS  PubMed  Google Scholar 

  49. Keiser J, Gruyer M-S, Perrottet N, Zanolari B, Mercier T, Decosterd L. Pharmacokinetic parameters of artesunate and dihydroartemisinin in rats infected with Fasciola hepatica. J Antimicrob Chemother. 2009;63(3):543–9. https://doi.org/10.1093/jac/dkn550.

    Article  CAS  PubMed  Google Scholar 

  50. Kongpatanakul S, Chatsiricharoenkul S, Sathirakul K, Suputtamongkol Y, Atipas S, Watnasirichaikul S, et al. Evaluation of the safety and relative bioavailability of a new dihydroartemisinin tablet formulation in healthy Thai volunteers. Trans R Soc Trop Med Hyg. 2007;101(10):972–9. https://doi.org/10.1016/j.trstmh.2007.05.010.

    Article  CAS  PubMed  Google Scholar 

  51. Kumar A, Valecha N, Jain T, Dash AP. Burden of malaria in India: retrospective and prospective view. Am J Trop Med Hyg. 2007;77(6 Suppl):69–78.

    PubMed  Google Scholar 

  52. Li QG, Peggins JO, Fleckenstein LL, Masonic K, Heiffer MH, Brewer TG. The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats. J Pharm Pharmacol. 1998;50(2):173–82. https://doi.org/10.1111/j.2042-7158.1998.tb06173.x.

    Article  CAS  PubMed  Google Scholar 

  53. Li Q, Xie LH, Si Y, Wong E, Upadhyay R, Yanez D, et al. Toxicokinetics and hydrolysis of artelinate and artesunate in malaria-infected rats. Int J Toxicol. 2005;24(4):241–50. https://doi.org/10.1080/10915810591007201.

    Article  PubMed  Google Scholar 

  54. Lisewski AM, Quiros JP, Ng CL, Adikesavan AK, Miura K, Putluri N, et al. Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell. 2014;158(4):916–28. https://doi.org/10.1016/j.cell.2014.07.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu Y, Hu M. Absorption and metabolism of flavonoids in the Caco-2 cell culture model and a perused rat intestinal model. Drug Metab Dispos. 2002;30(4):370–7. https://doi.org/10.1124/dmd.30.4.370.

    Article  CAS  PubMed  Google Scholar 

  56. Liwang C, Xin-zhuan S. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti-Infect Ther. 2009;7(8):999–1013.

    Article  Google Scholar 

  57. Mebrahtu E. Antimalarial drug resistance: in the past, current status and future perspectives. Br J Pharmacol Toxicol. 2015;6(1):1–15.

    Article  Google Scholar 

  58. Morris CA, Durpac S, Borghini-Fuhrer I, UngD J, Shin CS, Fleckenstein L. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J. 2011;10(1):263–81. https://doi.org/10.1186/1475-2875-10-263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Morris CA, Tan B, Duparc S, Borghini-Fuhrer I, Jung D, Shin CS, et al. Effect of body size and gender in the population pharmacokinetics of artesunate and its active metabolite DHA in paediatric malaria patients. Antimicrob Agents Chemother. 2013;57(12):5889–900. https://doi.org/10.1128/AAC.00635-13.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Mu J, Ferdig MT, Feng X, Joy DA, Duan J, Furuya T, et al. Multiple transporters associated with malaria parasite responses to chloroquine and quinine. Mol Microbiol. 2003;49(4):977–89. https://doi.org/10.1046/j.1365-2958.2003.03627.x.

    Article  CAS  PubMed  Google Scholar 

  61. Navaratnam V, Mansor MM, Sit NW, Grace J, Li Q, Olliaro P. Clin Pharmacokinet. 2000;39:255–70.

    Article  CAS  PubMed  Google Scholar 

  62. Ngo TH, Quintens I, Roets E, Declerck PJ, Hoogmartens J. Bioavailability of different artemisinin tablet formulations in rabbit plasma—correlation with results obtained by an in vitro dissolution method. J Pharm Biomed Anal. 1997;16(2):185–9. https://doi.org/10.1016/S0731-7085(97)00033-2.

    Article  CAS  PubMed  Google Scholar 

  63. Nkereuwem E, Samuel G, Adikwu E, Nelson O. Artemisinin and biomolecules: the continuing search for mechanism of action. Mol Cell Pharmacol. 2013;5(2):75–89.

    Google Scholar 

  64. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Artemisinin resistance in Cambodia 1 (ARC1) study consortium. N Engl J Med. 2008;359(24):2619–20. https://doi.org/10.1056/NEJMc0805011.

    Article  CAS  PubMed  Google Scholar 

  65. Olliaro PL, Nair NK, Sathasivam K, Mansor SM, Navaratnam V. Pharmacokinetics of artesunate after single oral administration to rats. BMC Pharmacol. 2001b;1(1):12. https://doi.org/10.1186/1471-2210-1-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Olowe OA, Makanjuola OB, Awa AO, Olowe RA. Malaria in Africa and the historical perspective: the journey so far. J Biol Med Sci. 2015;3:33–41.

    Google Scholar 

  67. Phyo AP, Nkhoma S, Stepniewska K. Emergence of artemisinin malaria on western border of Thailand: a longitudinal study. Lancet. 2012;379(9830):1960–96. https://doi.org/10.1016/S0140-6736(12)60484-X.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Pillay P. Malaria and antimalarials from plants. South Africa: University of Pretoria Edn; 2006. p. 1–20.

    Google Scholar 

  69. Qin C, Dennis EK, Michelle LG. Artemisinin resistance in P. falciparum: a process linked to dormancy? Int J Parasitol. 2012;2:249–55.

    Google Scholar 

  70. Qutob S, Dixon SJ, Wilson JX. Insulin stimulates vitamin C recycling and ascorbate accumulation in osteoblastic cells. Endocrinology. 1998;139(1):51–6. https://doi.org/10.1210/endo.139.1.5659.

    Article  CAS  PubMed  Google Scholar 

  71. Raj DK, Mu J, Jiang H, Kabat J, Singh S, Sullivan M, et al. Disruption of a P. falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione. J Biol Chem. 2009;284(12):7687–96. https://doi.org/10.1074/jbc.M806944200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ramu K, Baker JK. Synthesis, characterization, and antimalarial activity of the glucuronides of the hydroxylated metabolites of arteether. J Med Chem. 1995;38(11):1911–21. https://doi.org/10.1021/jm00011a011.

    Article  CAS  PubMed  Google Scholar 

  73. Reyburn H. New WHO guidelines for the treatment of malaria. BMJ. 2010;340:2637.

    Article  Google Scholar 

  74. Richard I, Kevin M, Chandy CJ, Charles RJ. Cerebral malaria: mechanisms of brain injury and strategies for improved neuro-cognitive outcome. Pediatr Res. 2010;68(4):267–74.

    Article  Google Scholar 

  75. Robert V, Awono AH, Hesran J, Trape J. Gametocytemia and infectivity to mosquitoes of patients with uncomplicated P. falciparum malaria attacks treated with chloroquine or sulfadoxine plus pyrimethamine. A J Trop Med Hyg. 2001;62:210–6.

    Article  Google Scholar 

  76. Rogers WO, Sem R, Tero T, Chim P, Lim P, Muth S. Failure of artesunate-mefloquine combination therapy for uncompleted P. falciparum malaria in South Cambodia. Malaria. 2009;8(10):33–45.

    Google Scholar 

  77. Roll Back Malaria Partnership. Climate change and malaria. Retrieved on March 16, 2017 from http://www.rollbackmalaria.org/files/files/about/SDGs/RBM_Climate_Change_Fact%20S heet_170915.pdf.

  78. Sachel M, Elizabeth AA, Pedro EF, Lei Z, Zhaoting L, Tomas Y, et al. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science. 2015;347:431–5.

    Article  Google Scholar 

  79. Salman S, Page-Sharp M, Batty KT, Kose K, Griffin S, Siba PM, et al. Pharmacokinetic comparison of two piperaquine-containing artemisinin combination therapies in Papua new Guinean children with uncomplicated malaria. Antimicrob Agents Chemother. 2012;56(6):3288–97. https://doi.org/10.1128/AAC.06232-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sanchez CP, Rotmann A, Stein WD, Lanzer M. Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in P. falciparum. Mol Microbiol. 2008;70(4):786–98. https://doi.org/10.1111/j.1365-2958.2008.06413.x.

    CAS  PubMed  Google Scholar 

  81. Santos-Magalhães NS, Mosqueira VC. Nanotechnology applied to the treatment of malaria. Adv Drug Del Rev. 2010;62(4-5):560–75. https://doi.org/10.1016/j.addr.2009.11.024.

    Article  Google Scholar 

  82. Satyajit T, Somenath R. A review of age-old antimalarial drug to combat malaria: efficacy upgradation by nanotechnology based drug delivery. Asian Pacif J Trop Med. 2014:673–9.

  83. Simpson JA, Agbenyega T, Barnes KI, Di Perri G, Folb P, Gomes M, et al. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med. 2006;3:2113–23.

    Article  CAS  Google Scholar 

  84. Srinivas NR. Is there a differential conversion of artesunate to dihydroartemisinin in pregnant vs. post- partum patients with malaria after oral artesunate dosing? Br J Clin Pharmacol. 2016;81(2):389–90. https://doi.org/10.1111/bcp.12809.

    Article  PubMed  Google Scholar 

  85. Takala-Harrison S, Clark TG, Jacob CG, Cummings MP, Miotto O, Dondorp AM, et al. Genetic loci associated with delayed clearance of P.falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci U S A. 2013;110(1):240–5. https://doi.org/10.1073/pnas.1211205110.

    Article  CAS  PubMed  Google Scholar 

  86. Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, et al. Multidrug-resistant P. vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia. PLoS Med. 2008;5:122–8.

    Article  Google Scholar 

  87. Tsai YM, Jan WC, Chien CF, Lee WC, Lin LC, Tsai TH. Optimised nano-formulation on the bioavailability of hydrophobic polyphenol, curcumin, in freely-moving rats. Food Chem. 2011;127(3):918–25. https://doi.org/10.1016/j.foodchem.2011.01.059.

    Article  CAS  PubMed  Google Scholar 

  88. Turschner S, Efferth T. Drug resistance in plasmodium: natural products in the fight against malaria. Mini-Rev Med Chem. 2009;9(2):206–14. https://doi.org/10.2174/138955709787316074.

    Article  CAS  PubMed  Google Scholar 

  89. Ugwu OP, OF N, Joshua PE, Odo CE, Ossai EC, Bawa A. Ameliorative effects of ethanol leaf extract of Moringa oleifera on the liver and kidney markers of malaria infected mice. Int J Life Sci Biotechnol Pharm Res. 2013;2(2):43–52.

    Google Scholar 

  90. White NJ. Antimalarial drug resistance. J Clin Invest. 2004;113(8):1084–92. https://doi.org/10.1172/JCI21682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. White N. Qinghaosu (artemisinin): the price of success. Science. 2008;320(5874):330–4. https://doi.org/10.1126/science.1155165.

    Article  CAS  PubMed  Google Scholar 

  92. WHO. Africa summit on roll back Malaria. Summary Report, Malsum Inbrief, Abuja, Nigeria. http://savekids.dzopus.org/pdfs/African%20Summit%20on%20Roll%20Back%20Malaria. pdf. 2000.

  93. WHO. World Malaria Report. http://apps.who.int/iris/bitstream/10665/43939/1/9789241563697_eng.pdf. 2008.

  94. WHO. World Malaria Report 2012. www.who.int/malaria/publications/world_malaria_report_2012/en/. 2012.

  95. WHO. Status report on artemisinin and ACT resistance September 2015. Global Malaria Programme, World Health Organization (WHO). (http://www.who.int/malaria/publications/atoz/status-rep-artemisinin-resistancesept2015.pdf?ua=1). 2015a.

  96. WHO. Status report on artemisinin and ACT resistance September 2015 http://www.who.int/malaria/publications/atoz/status-rep-artemisinin- resistancesept2015.pdf. 2015b.

  97. WHO/CDS/CSR/DRS/2001.4 World Health Organization Department of Communicable Disease Surveillance and Response Drug resistance in malaria http://www.who.int/csr/resources/publications/drugresist/malaria.pdf. 2001.

  98. WHO/HTM/GMP/2014.3 Emergence and spread of artemisinin resistance calls for intensified efforts to withdraw oral artemisinin-based monotherapy from the market 1 May 2014 Key messages In January 2014, the WHO Global Malaria Programme published the latest status report on artemisinin resistance. 2014.

  99. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J. 2005;81(952):71–8. World Health Organization, 2011. World malaria report 2011. https://doi.org/10.1136/pgmj.2004.028399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Xiaonan Z. Protein binding determination of dihydroartemisinin (DHA) in human plasma by HPLC using post-column on-line alkali derivatization and UV detection. Retrieved on April 03, 2017 from http://publications.lib.chalmers.se/records/fulltext/126728.pdf. 2009.

  101. Xie LH, Lisa H, Qigui L, Zhang J, Weina PJ. Pharmacokinetic tissue distribution and mass balance of radiolabeled DHA in male rats. Malaria J. 2009;8:112.

    Article  Google Scholar 

  102. Xie X, Tao Q, Zou Y, Zhang F, Guo M, Wang Y, et al. PLGA nanoparticles improve the oral bioavailability of curcumin in rats: characterizations and mechanisms. J Agric Food Chem. 2011;59(17):9280–9. https://doi.org/10.1021/jf202135j.

    Article  CAS  PubMed  Google Scholar 

  103. Xu H, Kulkarmi KH, Sing R, Zhen Y, Wang SWJ, Tam VH, et al. Disposition of Naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucoronides. Mol Pharm (NIH public access). 2009;6(6):1703–15. https://doi.org/10.1021/mp900013d.

    Article  CAS  Google Scholar 

  104. Yang Z, Gao S, Wang J, Yin T, Teng Y, Wu B, et al. Enhancement of oral bioavailability of 20(S)- ginsenoside Rh2 through improved understanding of its absorption and efflux mechanisms. Drug Metab Dispos. 2011;39(10):1866–72. https://doi.org/10.1124/dmd.111.040006.

    Article  CAS  PubMed  Google Scholar 

  105. Zetterström R. Nobel prizes for discovering the cause of malaria and the means of bringing the disease under control: hopes and disappointments. Acta Paediatr. 2007;96(10):1546–50. https://doi.org/10.1111/j.1651-2227.2007.00452.x.

    Article  PubMed  Google Scholar 

  106. Zhu F, Du F, Li X, Xing J. Investigation of the auto-induction of and gender-related variability in the pharmacokinetics of dihydroartemisinin in the rat. Malar J. 2012;11(1):379–88. Retrieved on March 16, 2017 from http://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-11-379. https://doi.org/10.1186/1475-2875-11-379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhu W, Xu H, Wang SJ, Hu M. Breast Cancer Resistance Protein (BCRP) and sulfotransferases contribute significantly to the disposition of genistein in mouse intestine. The AAPS Journal 2010;12(4):525–36

  108. Zime-Diawara H, Gbaguidi F, Semde R, Leclercq JQ, Moudachirou M, Some I, et al. Effect of cyclodextrins on artemisinin stability and in vitro dissolution. Int J Biol Chem Sci. 2013;7(1):356–65.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant number GM070737 from the NIH.

Author information

Authors and Affiliations

  1. Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX, 77030, USA

    Uduma E. Osonwa & Ming Hu

  2. Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Nnamdi Azikiwe University, Awka, Nigeria

    Uduma E. Osonwa

Authors
  1. Uduma E. Osonwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uduma E. Osonwa.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Molecular Drug Disposition

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Osonwa, U.E., Hu, M. Bioavailability and Pharmacokinetics of Dihydroartemisinin (DHA) and its Analogs—Mechanistic Studies on its ADME. Curr Pharmacol Rep 4, 33–44 (2018). https://doi.org/10.1007/s40495-018-0120-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40495-018-0120-y

Keywords

Search

Navigation