Antimalarial interaction with ferriprotoporphyrin IX monomer and its relationship to activity of the blood schizontocides

Dc, Warhurst

doi:10.1080/00034983.1987.11812093

Cited by 33 publications

(11 citation statements)

References 5 publications

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“…The enlargement and pigmentation of the liver and spleen of rats in the present studies, appeared to vary with the severity of the infection produced. Since malaria pigment occupies spaces in the Kupffer cells and quinine and quinidine are reported to form complexes with ferriprotopophyrin IX to a certain extent (Fitch, 1986;Warhurst 1987) this might play a role in changing the distributional characteristic observed, especially with quinine, in this study.…”

Section: Discussionmentioning

confidence: 63%

The Effect of Malaria Infection on the Disposition of Quinine and Quinidine in the Rat Isolated Perfused Liver Preparation

Mansor

Ward

Edwards

et al. 1990

Journal of Pharmacy and Pharmacology

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The effect of malaria on the disposition of quinine and quinidine was studied in livers isolated from young rats infected with merozoites of Plasmodium berghei, a rodent malaria model, and non-infected controls. Following bolus administration of quinine (1 mg) or quinidine (1 mg) to the 100 mL recycling perfusion circuit, perfusate was sampled (0-4 h) and plasma assayed for quinine and quinidine by HPLC. Higher quinine (AUC:6470 +/- 1101 vs 3822 +/- 347 ng h mL-1, P less than 0.001) and quinidine (AUC: 6642 +/- 1304 vs 4808 +/- 872 ng h mL-1, P less than 0.05) concentrations were observed during malaria infection (MI). MI resulted in decreased quinine clearance (CL) (0.33 +/- 0.08 vs 0.64 +/- 0.09 mL min-1 g-1, P less than 0.001) and volume of distribution (Vd) (53.0 +/- 13.3 vs 81.2 +/- 23.7 mL g-1, P less than 0.05) but no significant change in elimination half-life (t1/2) (1.93 +/- 0.6 vs 1.37 +/- 0.25 h, P greater than 0.05). With quinidine, however, MI resulted in decreased CL (0.38 +/- 0.16 vs 0.64 +/- 0.09, P less than 0.05) with no change in Vd and a significant increase in t1/2 (1.62 +/- 0.42 vs 0.88 +/- 0.22, P less than 0.01). In summary, the hepatic disposition of quinine and quinidine is altered in the malaria-infected rat.

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Section: Discussionmentioning

confidence: 63%

The Effect of Malaria Infection on the Disposition of Quinine and Quinidine in the Rat Isolated Perfused Liver Preparation

Mansor

Ward

Edwards

et al. 1990

Journal of Pharmacy and Pharmacology

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“…36,37 Complexes of a drug with ferriprotoporphyrin IX could prevent incorporation of heme into hemozoin resulting in the observed toxic effects. 38 Since the complexes of chloroquine and ferriprotoporphyrin IX can lyse membranes, the aminoquinoline-heme complexes 39 have been proposed as the causative cytotoxic agents. Furthermore, since these complexes can only be formed in malaria-infected red cells, they are good candidates for accounting for the selective toxicity of aminoquinolines such as amodiaquine and chloroquine.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, Antimalarial Activity, and Molecular Modeling of Tebuquine Analogues

et al. 1997

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Tebuquine (5) is a 4-aminoquinoline that is significantly more active than amodiaquine (2) and chloroquine (1) both in vitro and in vivo. We have developed a novel more efficient synthetic route to tebuquine analogues which involves the use of a palladium-catalyzed Suzuki reaction to introduce the 4-chlorophenyl moiety into the 4-hydroxyaniline side chain. Using similar methodology, novel synthetic routes to fluorinated (7a, b) and a dehydroxylated (7c) analogue of tebuquine have also been developed. The novel analogues were subjected to testing against the chloroquine sensitive HB3 strain and the chloroquine resistant K1 strain of Plasmodium falciparum. Tebuquine was the most active compound tested against both strains of Plasmodia. Replacement of the 4-hydroxy function with either fluorine or hydrogen led to a decrease in antimalarial activity. Molecular modeling of the tebuquine analogues alongside amodiaquine and chloroquine reveals that the inter-nitrogen separation in this class of drugs ranges between 9.36 and 9.86 A in their isolated diprotonated form and between 7.52 and 10.21 A in the heme-drug complex. Further modeling studies on the interaction of 4-aminoquinolines with the proposed cellular receptor heme revealed favorable interaction energies for chloroquine, amodiaquine, and tebuquine analogues. Tebuquine, the most potent antimalarial in the series, had the most favorable interaction energy calculated in both the in vacuo and solvent-based simulation studies. Although fluorotebuquine (7a) had a similar interaction energy to tebuquine, this compound had significantly reduced potency when compared with (5). This disparity is possibly the result of the reduced cellular accumulation (CAR) of fluorotebuquine when compared with tebuquine within the parasite. Measurement of the cellular accumulation of the tebuquine analogues and seven related 4-aminoquinolines shows a significant relationship (r = 0.98) between the CAR of 4-aminoquinoline drugs and the reciprocal of drugs IC50.

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“…This complex can damage various cellular structures and/or inhibit hemoglobin-degrading enzymes. However, this mechanism cannot explain the lack of correlation between the affinities of various antimalarial drugs (particularly amodiaquine) for ferriprotoporphyrin IX and their rank order of activities (Warhurst, 1987). In agreement with this earlier hypothesis, Slater and Cerami (1992) described a catalytic activity able to induce the polymerization of ferriprotoporphyrin IX into the malaria pigment of P falciparum-infected erythrocytes.…”

Section: Introductionmentioning

confidence: 92%

Antimalarial 4‐aminoquinolines: mode of action and pharmacokinetics

Pussard

Verdier

1994

Fundamemntal Clinical Pharma

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In the last ten years, the widespread increase in Plasmodium falciparum resistance to chloroquine has prompted research into antimalarial 4-aminoquinolines, empirically used up to now. The mechanism of action of 4-aminoquinolines is characterized by the concentration of the drug in the digestive vacuole of the intraerythrocytic parasite. Various hypotheses have been advanced to explain the specificity of action on the parasite; the most recent one is the inhibition of the haem polymerase of the parasite, leading to the accumulation of soluble haem toxic for the parasite. Chloroquine-resistant parasites accumulate the drug to a lesser extent than do sensitive parasites. Recent findings have shown that chloroquine resistance can be reversed by various tricyclic drugs, which are able to restore the effective concentrations of chloroquine in the infected erythrocyte, but intrinsic mechanisms of action of these reversing agents are unknown. Four-aminoquinolines are extensively distributed in tissues and characterized by a long elimination half-life. Despite similarities in their chemical structures, these drugs show differences in their biotransformation and routes of elimination: chloroquine is partly metabolized into a monodesethylderivative and eliminated mainly by the kidney. In contrast, amodiaquine is a prodrug and amopyroquine is poorly metabolized; both drugs are excreted mainly in the bile. The understanding of the pharmacokinetics of 4-aminoquinolines has led to an improvement in empirically defined therapeutic regimens. Finally, the emergence of severe adverse-effects after prolonged prophylaxis with amodiaquine and the lack of cross resistance of Plasmodium falciparum between chloroquine and amopyroquine, have led to a proposal for the use of intramuscular amopyroquine as an alternative for the treatment of chloroquine-resistant malaria.

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Antimalarial interaction with ferriprotoporphyrin IX monomer and its relationship to activity of the blood schizontocides

Cited by 33 publications

References 5 publications

The Effect of Malaria Infection on the Disposition of Quinine and Quinidine in the Rat Isolated Perfused Liver Preparation

The Effect of Malaria Infection on the Disposition of Quinine and Quinidine in the Rat Isolated Perfused Liver Preparation

Synthesis, Antimalarial Activity, and Molecular Modeling of Tebuquine Analogues

Antimalarial 4‐aminoquinolines: mode of action and pharmacokinetics

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