BOUREE P, FOUQUET E, BERNIER A, PUSSARD E; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. A-2191.
Parasitology Dept, Paris XI Univ, Bicetre, France
BACKGROUND: Malaria alters clearance and biotransformations of many drugs. The mechanisms of impairment of quinine (Qn) distribution in blood and tissues during malaria were investigated using a model of P. berghei infected mice. METHODS: The concentrations of Qn and its 3-OH metabolite were assessed by h.p.l.c. with fluorometric detection in blood and tissues after a single intraperitoneal injection of 80 mg.kg-1 of Qn to control mice and during moderate or severe P. berghei malaria. RESULTS: Kinetics parameters of blood Qn were determined in control (n=8), group 1 (parasitemia 9 +/- 6 %, n=8) and group 2 (parasitemia 31 +/- 6 %, n=8). As compared with control, AUC0-i of blood Qn (17 +/- 5 microg/ml.h) increases in groups 1 (35 +/- 13 microg/ml.h) and 2 (54 +/- 14 microg/ml.h). Qn blood clearance (153 +/- 31 l/h) and AUC0-i of 3-OHQn (15 +/- 4 microg/ml.h) decrease in group 1 (74 +/- 32 l/h and 12 +/- 3 microg/ml.h, respectively) and in group 2 (47 +/- 18 l/h and 8 +/- 4 microg/ml.h, respectively). In group 2, the distribution volume (Vd) of blood Qn (162 +/- 45 l) is smaller than in control (213 +/- 53 l) and group 1 (230 +/- 65 l). Two hours after injection, Qn concentrations in blood fractions and tissues were determined in control (n=8), group 1 (parasitemia 11 +/- 6 %, n=25) and group 2 (parasitemia 34 +/- 9 %, n=22). The tissue-to-plasma free fraction ratio (Kp) of Qn in erythrocytes, spleen, lung and kidney increase in a parasitemia-dependent manner, suggesting a binding to high affinity sites. In the muscle, heart and liver, Kp are similar in control and infected mice, indicating a free fraction-dependent uptake. In the brain, Kp decreases with the rise of parasitemia underlying a limitation of uptake and/or an efflux of the drug. CONCLUSION: P. berghei malaria inhibits Qn metabolism in a parasitemia depending manner, resulting in a rise of blood Qn. Qn redistribution in tissues is heterogeneous and explains the reduction of Vd observed in severe malaria. P. berghei infection in mice is a usable model for further quinine studies.
Publication Types:
Keywords:
- Animals
- Cinchona
- Erythrocytes
- Injections, Intraperitoneal
- Malaria
- Malaria Vaccines
- Mice
- Mice, Inbred C57BL
- Muridae
- Parasitemia
- Plasmodium berghei
- Quinine
- blood
- methods
- pharmacokinetics
Other ID:
UI: 102268588
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