A study of the factors affecting the metabolic clearance of quinine in malaria.
OBJECTIVE
To assess the factors that contribute to impaired quinine clearance in acute falciparum malaria.


METHODS
Sixteen adult Thai patients with severe or moderately severe falciparum malaria were studied, and 12 were re-studied during convalescence.


METHODS
The clearance of quinine, dihydroquinine (an impurity comprising up to 10% of commercial quinine formulations), antipyrine (a measure of hepatic mixed-function oxidase activity), indocyanine green (ICG) (a measure of liver blood flow), and iothalamate (a measure of glomerular filtration rate) were measured simultaneously, and the relationship of these values to the biotransformation of quinine to the active metabolite 3-hydroxyquinine was assessed.


RESULTS
During acute malaria infection, the systemic clearance of quinine, antipyrine and ICG and the biotransformation of quinine to 3-hydroxyquinine were all reduced significantly when compared with values during convalescence. Iothalamate clearance was not affected significantly and did not correlate with the clearance of any of the other compounds. The clearance of total and free quinine correlated significantly with antipyrine clearance (rs = 0.70, P = 0.005 and rs = 0.67, P = 0.013, respectively), but not with ICG clearance (rs = 0.39 and 0.43 respectively, P > 0.15). In a multiple regression model, antipyrine clearance and plasma protein binding accounted for 71% of the variance in total quinine clearance in acute malaria. The pharmacokinetic properties of dihydroquinine were generally similar to those of quinine, although dihydroquinine clearance was less affected by acute malaria. The mean ratio of quinine to 3-hydroxyquinine area under the plasma concentration-time curve (AUC) values in acute malaria was 12.03 compared with 6.92 during convalescence P = 0.01. The mean plasma protein binding of 3-hydroxyquinine was 46%, which was significantly lower than that of quinine (90.5%) or dihydroquinine (90.5%).


CONCLUSIONS
The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of quinine to its major metabolite, 3-hydroxyquinine. The metabolite contributes approximately 5% of the antimalarial activity of the parent compound in malaria, but up to 10% during convalescence.
Pukrittayakamee
S
S
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Looareesuwan
S
S
Keeratithakul
D
D
Davis
T M
TM
Teja-Isavadharm
P
P
Nagachinta
B
B
Weber
A
A
Smith
A L
AL
Kyle
D
D
White
N J
NJ
D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D005260:Female; D006207:Half-Life; D006801:Humans; D007208:Indocyanine Green / Q000493:pharmacokinetics; D007483:Iothalamic Acid / Q000493:pharmacokinetics; D016778:Malaria, Falciparum / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010963:Plasmodium falciparum; D011803:Quinine / Q000493:pharmacokinetics*
D000962:Antimalarials; D007483:Iothalamic Acid; D011803:Quinine; D007208:Indocyanine Green; D000983:Antipyrine