- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- Dose formulation analysis.
- Pharmacokinetics of [14C] artesunate, unchanged artesunate, and dihydroartemisinin.
- Tissue distribution of [14C] artesunate.
- Mass balance determination.
- Urinary and fecal elimination.
- Metabolite profiles of [14C] artesunate.
- Protein binding of [14C] artesunate with rat and human plasma.
- DISCUSSION
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1
World Health Organization, 1990. Control of tropical diseases. Severe and complicated malaria. Trans R Soc Trop Med Hyg 84 (Suppl 2): 1–65.
-
2
de Vries PJ, Dien TK, 1996. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 52 :818–836.
-
3
Li QG, Brewer TG, Peggins JO, 1998. Anorectic toxicity of di-hydroartemisinin, arteether and artemether in rats following multiple intramuscular doses. Int J Toxicol 17 :663–676.
-
4
Li QG, Mog SR, Si YZ, Kyle DE, Gettayacamin M, Milhous WK, 2002. Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents. Am J Trop Med Hyg 66 :516–525.
-
5
McLean WG, Ward SA, 1998. In vitro neurotoxicity of artemisinin derivatives. Med Trop 58 (Suppl 3):28S–31S.
-
6
Wesche DL, DeCoster MA, Tortella FC, Brewer TG, 1994. Neurotoxicity of artemisinin analogs in vitro. Antimicrob Agents Chemother 38 :1813–1819.
-
7
Skinner TS, Manning LS, Johnston W, Davis TME, 1996. In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs. Int J Parasit 26 :519–525.
-
8
Davis TM, Phuong HL, Ilett KF, Hung NC, Batty KT, Phuong VD, Powell SM, Thien HV, Binh TQ, 2001. Pharmacokinetics and pharmacodynamics of IV artesunate in severe falciparum malaria. Antimicrob Agents Chemother 45 :181–186.
-
9
Batty KT, Le AT, Ilett KF, Nguyen PT, Powell SM, Nguyen CH, Truong XM, Vuong VC, Huynh VT, Tran QB, Nguyen VM, Davis TM, 1998. A pharmacokinetic and pharmacodynamic study of artesunate for vivax malaria. Am J Trop Med Hyg 59 :823–827.
-
10
Newton P, Suputtamongkol Y, Teja-Isavadiharm P, Pukrittay-akamee S, Navaratnam V, Bates I, White N, 2000. Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrob Agents Chemother 44 :972–977.
-
11
Bethell DB, Teja-Isavadharm P, Cao XT, Pham TT, Ta TT, Tran TN, Nguyen TT, Pham TP, Kyle D, Day NP, White NJ, 1997. Pharmacokinetics of oral artesunate in children with moderately severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 91 :195–198.
-
12
Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST, 1997. Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg 56 :17–23.
-
13
Na-Bangchang K, Karbwang J, Congpoung K, Thanavibul A, Ubalee R, 1998. Pharmacokinetics and bioequivalence evaluation of two generic formulations of oral artesunate. Eur J Clin Pharmacol 53 :375–376.
-
14
Li QG, Peggins JO, Lin AJ, Masonic K, Trotman KM, Brewer TG, 1998. Pharmacology and toxicology of artelinic acid: Pre-clinical investigation on pharmacokinetics, metabolism, protein and RBC binding, acute and anorectic toxicities. Trans R Soc Trop Med Hyg 92 :332–340.
-
15
Titulaer HA, Eling WM, Zuidema J, 1993. Pharmacokinetic and pharmacodynamic aspects of artelinic acid in rodents. J Pharm Pharmacol 45 :830–835.
-
16
Batty KT, Thu TA, Davis TM, Ilett KF, Mai TX, Hung NC, Tien NP, Powell MS, Thien HV, Binh TQ, Kim NV, 1998. A pharmacokinetic and pharmacodynamic study of IV vs oral AS in uncomplicated falciparum malaria. Br J Clin Pharmacol 45 :123–129.
-
17
Li QG, Peggins JO, Fleckenstein L, Masonic K, Heiffer MH, Brewer TG, 1998. Bioavailability and pharmacokinetics of di-hydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats. J Pharm Pharmacol 50 :173–182.
-
18
Li QG, Carpenter C, Trotman C, Kathcart AK, Donahue R, Milhous WK, 1999. Pharmacokinetic comparison of artesunate and dihydroartemisinin in beagle dogs. Am J Trol Med Hyg 61 :274.
-
19
Brewer TG, Grate SJ, Peggins JO, Weina PJ, Petras JM, Levine BS, Heiffer MH, Schuster BG, 1994. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 51 :251–259.
-
20
Classen W, Altmann B, Gretener P, Souppart C, Skelton-Stroud P, Krinke G, 1999. Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs. Exp Toxicol Pathol 51 :507–516.
-
21
Genovese RF, Newman DB, Petras JM, Brewer TG, 1998. Behavioral and neural toxicity of arteether in rats. Pharmacol Biochem Behav 60 :449–458.
-
22
Petras JM, Kyle DE, Gettayacamin M, Young GD, Bauman RA, Webster HK, Corcoran KD, Peggins JO, Vane MA, Brewer TG, 1997. Arteether: Risks of two-week administration in Macaca mulatta. Am J Trop Med Hyg 56 :390–396.
-
23
Smith SL, Sadler CJ, Dodd CC, Edwards G, Ward SA, Park BK, McLean WG, 2001. The role of glutathione in the neurotoxicity of artemisinin derivatives in vitro. Biochem Pharmacol 61 :409–416.
-
24
Nui XY, Ho LY, Ren ZH, Song ZY, 1985. Metabolic fate of qinghaosu in rats: a new TLC densitometric method for its determination in biological material. Eur J Drug Metab Pharmacokinet 10 :55–59.
-
25
Kearney BP, Aweeka FT, 1999. The penetration of anti-infectives into the central nervous system. Neurol Clin 17 :883–900.
-
26
Zhao KC, Song ZY, 1989. Distribution and excretion of artesunate in rats. Proc Chin Acad Med Sci 4 :186–188.
-
27
Tian F, Zhu Y, Long H, Cregor M, Xie F, Kissinger CB, Kissinger PT, 2002. Liquid chromatography coupled with multi-channel electrochemical detection for the determination of daidzein in rat blood sampled by an automated blood sampling system. J Chromatogr B Analyt Technol Biomed Life Sci 772 :173–177.
-
28
Li QG, Hümpel M, 1990. Serum protein binding characteristics of cyproterone acetate, gestodene, levonorgestrel and norethisterone in rat, rabbit, dog, monkey and man. J Steroid Biochem 35 :319–326.
-
29
China Cooperative Research Group on Qinghaosu and its Derivatives as Antimalarials, 1982. Metabolism and pharmacokinetics of qinghaosu and its derivatives. J Trad Chin Med 2 :25–30.
-
30
Maggs JL, Madden S, Bishop LP, O’Neill PM, Park BK, 1997. The rat biliary metabolites of dihydroartemisinin, an antimalarial endoperoxide. Drug Metab Dispos 10 :1200–1204.
-
31
Pollack GM, Brouwer KLR, Demby KB, Jones JA, 1990. Determination of hepatic blood flow in the rat using sequential infusions of indocyanine green and galactose. Drug Metab Dispos 18 :197–202.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 217 | 162 | 17 |
| Full Text Views | 382 | 4 | 1 |
| PDF Downloads | 124 | 4 | 1 |
THE EVALUATION OF RADIOLABELED ARTESUNATE ON TISSUE DISTRIBUTION IN RATS AND PROTEIN BINDING IN HUMANS
QIGUI LI
QIGUI LI
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland
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LISA H. XIE
LISA H. XIE
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland
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ADAM HAEBERLE
ADAM HAEBERLE
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland
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JING ZHANG
JING ZHANG
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland
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PETER WEINA
PETER WEINA
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland
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The present study reports the tissue distribution, pharmacokinetics, mass balance, and elimination of [14C] artesunate (AS) following single intravenous administration in rats. Protein binding was performed with rat and human plasma. Radioactivity and drug levels in blood, plasma, tissues, urine, and feces up to 192 hours were collected and measured. The mean terminal half-life of plasma (76 h) and blood (105 h) radioactivity was prolonged compared with that of unchanged AS (0.43 h) and dihydroartemisinin (0.75 h), an active metabolite of AS. Drug was widely distributed after 1 hour in select tissues. After 24 hours, the radioactivity rapidly declined in all tissues except spleen until 96 hours. Only 1% of total radioactivity was detected in brain tissue. AS revealed a higher binding capacity with human and rat plasma proteins (73–81%). The radioactivity in whole blood was higher (two to fourfold) than that in plasma throughout the period of the treatment, suggesting that AS binding to RBCs may relate to its powerful antimalarial activity.
Author Notes
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- Dose formulation analysis.
- Pharmacokinetics of [14C] artesunate, unchanged artesunate, and dihydroartemisinin.
- Tissue distribution of [14C] artesunate.
- Mass balance determination.
- Urinary and fecal elimination.
- Metabolite profiles of [14C] artesunate.
- Protein binding of [14C] artesunate with rat and human plasma.
- DISCUSSION
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1
World Health Organization, 1990. Control of tropical diseases. Severe and complicated malaria. Trans R Soc Trop Med Hyg 84 (Suppl 2): 1–65.
-
2
de Vries PJ, Dien TK, 1996. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 52 :818–836.
-
3
Li QG, Brewer TG, Peggins JO, 1998. Anorectic toxicity of di-hydroartemisinin, arteether and artemether in rats following multiple intramuscular doses. Int J Toxicol 17 :663–676.
-
4
Li QG, Mog SR, Si YZ, Kyle DE, Gettayacamin M, Milhous WK, 2002. Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents. Am J Trop Med Hyg 66 :516–525.
-
5
McLean WG, Ward SA, 1998. In vitro neurotoxicity of artemisinin derivatives. Med Trop 58 (Suppl 3):28S–31S.
-
6
Wesche DL, DeCoster MA, Tortella FC, Brewer TG, 1994. Neurotoxicity of artemisinin analogs in vitro. Antimicrob Agents Chemother 38 :1813–1819.
-
7
Skinner TS, Manning LS, Johnston W, Davis TME, 1996. In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs. Int J Parasit 26 :519–525.
-
8
Davis TM, Phuong HL, Ilett KF, Hung NC, Batty KT, Phuong VD, Powell SM, Thien HV, Binh TQ, 2001. Pharmacokinetics and pharmacodynamics of IV artesunate in severe falciparum malaria. Antimicrob Agents Chemother 45 :181–186.
-
9
Batty KT, Le AT, Ilett KF, Nguyen PT, Powell SM, Nguyen CH, Truong XM, Vuong VC, Huynh VT, Tran QB, Nguyen VM, Davis TM, 1998. A pharmacokinetic and pharmacodynamic study of artesunate for vivax malaria. Am J Trop Med Hyg 59 :823–827.
-
10
Newton P, Suputtamongkol Y, Teja-Isavadiharm P, Pukrittay-akamee S, Navaratnam V, Bates I, White N, 2000. Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrob Agents Chemother 44 :972–977.
-
11
Bethell DB, Teja-Isavadharm P, Cao XT, Pham TT, Ta TT, Tran TN, Nguyen TT, Pham TP, Kyle D, Day NP, White NJ, 1997. Pharmacokinetics of oral artesunate in children with moderately severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 91 :195–198.
-
12
Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST, 1997. Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg 56 :17–23.
-
13
Na-Bangchang K, Karbwang J, Congpoung K, Thanavibul A, Ubalee R, 1998. Pharmacokinetics and bioequivalence evaluation of two generic formulations of oral artesunate. Eur J Clin Pharmacol 53 :375–376.
-
14
Li QG, Peggins JO, Lin AJ, Masonic K, Trotman KM, Brewer TG, 1998. Pharmacology and toxicology of artelinic acid: Pre-clinical investigation on pharmacokinetics, metabolism, protein and RBC binding, acute and anorectic toxicities. Trans R Soc Trop Med Hyg 92 :332–340.
-
15
Titulaer HA, Eling WM, Zuidema J, 1993. Pharmacokinetic and pharmacodynamic aspects of artelinic acid in rodents. J Pharm Pharmacol 45 :830–835.
-
16
Batty KT, Thu TA, Davis TM, Ilett KF, Mai TX, Hung NC, Tien NP, Powell MS, Thien HV, Binh TQ, Kim NV, 1998. A pharmacokinetic and pharmacodynamic study of IV vs oral AS in uncomplicated falciparum malaria. Br J Clin Pharmacol 45 :123–129.
-
17
Li QG, Peggins JO, Fleckenstein L, Masonic K, Heiffer MH, Brewer TG, 1998. Bioavailability and pharmacokinetics of di-hydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats. J Pharm Pharmacol 50 :173–182.
-
18
Li QG, Carpenter C, Trotman C, Kathcart AK, Donahue R, Milhous WK, 1999. Pharmacokinetic comparison of artesunate and dihydroartemisinin in beagle dogs. Am J Trol Med Hyg 61 :274.
-
19
Brewer TG, Grate SJ, Peggins JO, Weina PJ, Petras JM, Levine BS, Heiffer MH, Schuster BG, 1994. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 51 :251–259.
-
20
Classen W, Altmann B, Gretener P, Souppart C, Skelton-Stroud P, Krinke G, 1999. Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs. Exp Toxicol Pathol 51 :507–516.
-
21
Genovese RF, Newman DB, Petras JM, Brewer TG, 1998. Behavioral and neural toxicity of arteether in rats. Pharmacol Biochem Behav 60 :449–458.
-
22
Petras JM, Kyle DE, Gettayacamin M, Young GD, Bauman RA, Webster HK, Corcoran KD, Peggins JO, Vane MA, Brewer TG, 1997. Arteether: Risks of two-week administration in Macaca mulatta. Am J Trop Med Hyg 56 :390–396.
-
23
Smith SL, Sadler CJ, Dodd CC, Edwards G, Ward SA, Park BK, McLean WG, 2001. The role of glutathione in the neurotoxicity of artemisinin derivatives in vitro. Biochem Pharmacol 61 :409–416.
-
24
Nui XY, Ho LY, Ren ZH, Song ZY, 1985. Metabolic fate of qinghaosu in rats: a new TLC densitometric method for its determination in biological material. Eur J Drug Metab Pharmacokinet 10 :55–59.
-
25
Kearney BP, Aweeka FT, 1999. The penetration of anti-infectives into the central nervous system. Neurol Clin 17 :883–900.
-
26
Zhao KC, Song ZY, 1989. Distribution and excretion of artesunate in rats. Proc Chin Acad Med Sci 4 :186–188.
-
27
Tian F, Zhu Y, Long H, Cregor M, Xie F, Kissinger CB, Kissinger PT, 2002. Liquid chromatography coupled with multi-channel electrochemical detection for the determination of daidzein in rat blood sampled by an automated blood sampling system. J Chromatogr B Analyt Technol Biomed Life Sci 772 :173–177.
-
28
Li QG, Hümpel M, 1990. Serum protein binding characteristics of cyproterone acetate, gestodene, levonorgestrel and norethisterone in rat, rabbit, dog, monkey and man. J Steroid Biochem 35 :319–326.
-
29
China Cooperative Research Group on Qinghaosu and its Derivatives as Antimalarials, 1982. Metabolism and pharmacokinetics of qinghaosu and its derivatives. J Trad Chin Med 2 :25–30.
-
30
Maggs JL, Madden S, Bishop LP, O’Neill PM, Park BK, 1997. The rat biliary metabolites of dihydroartemisinin, an antimalarial endoperoxide. Drug Metab Dispos 10 :1200–1204.
-
31
Pollack GM, Brouwer KLR, Demby KB, Jones JA, 1990. Determination of hepatic blood flow in the rat using sequential infusions of indocyanine green and galactose. Drug Metab Dispos 18 :197–202.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 217 | 162 | 17 |
| Full Text Views | 382 | 4 | 1 |
| PDF Downloads | 124 | 4 | 1 |