Publication: A study of the factors affecting the metabolic clearance of quinine in malaria
Issued Date
1997-10-01
Resource Type
ISSN
00316970
Other identifier(s)
2-s2.0-9844226785
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Mahidol University
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SCOPUS
Bibliographic Citation
European Journal of Clinical Pharmacology. Vol.52, No.6 (1997), 487-493
Suggested Citation
S. Pukrittayakamee, S. Looareesuwan, D. Keeratithakul, T. M.E. Davis, P. Teja-Isavadharm, B. Nagachinta, A. Weber, A. L. Smith, D. Kyle, N. J. White A study of the factors affecting the metabolic clearance of quinine in malaria. European Journal of Clinical Pharmacology. Vol.52, No.6 (1997), 487-493. doi:10.1007/s002280050323 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/18073
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Title
A study of the factors affecting the metabolic clearance of quinine in malaria
Abstract
Objective: To assess the factors that contribute to impaired quinine clearance in acute falciparum malaria. Patients: Sixteen adult Thai patients with severe or moderately severs 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 (r(s) = 0.70, P = 0.005 and r(s) = 0.67, P = 0.013, respectively), but not with ICG clearance (r(s) = 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%). Conclusion: 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.