Effects of Plasmodium berghei infection on arteether metabolism and disposition.
Arteether (AE) is primarily deethylated to dihydroqinghaosu (DQHS) in rats and humans. Conversion of AE to DQHS was impaired in microsomes from rats infected with Plasmodium berghei. The Km for AE was 175.1 +/- 49.1 and 124.4 +/- 115.1 mumol/l, and Vmax was 2.24 +/- 0.45 and 1.22 +/- 0.67 nmol AE formed/mg protein/min in control and infected microsomes (p < 0.05), respectively. Calculated intrinsic clearance (CLint = initial Vmax/Km) for AE was only 4% lower in infected microsomes. Apparent pharmacokinetic parameter estimates for AE using the isolated perfused rat liver demonstrated no differences (p > 0.05) in volume of distribution, clearance, and half-life between normal and infected animals. Malaria infection resulted in decreased biliary excretion of free AE and DQHS. The majority of AE is eliminated via biliary excretion of conjugated DQHS, which is approximately 500-fold higher than free DQHS and 75-fold higher than free AE on a molar basis.
Leo
K U
KU
Department of Pharmacology, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, USA. MAJ-Kathleen-Leo@WRSMTP-cemail.army.mil
Grace
J M
JM
Li
Q
Q
Peggins
J
J
Mitchell
A L
AL
Aguilar
T
T
Brewer
T G
TG
D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D037621:Artemisinins; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006207:Half-Life; D007553:Isotope Labeling; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010477:Perfusion; D010962:Plasmodium berghei; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D014018:Tissue Distribution
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C039060:artenimol; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase; C055141:artemotil