Showing papers by "B.K. Park published in 1998"

Metabolism-dependent neutrophil cytotoxicity of amodiaquine: A comparison with pyronaridine and related antimalarial drugs

Abstract: Life-threatening agranulocytosis and hepatotoxicity during prophylactic administration of amodiaquine have led to its withdrawal. Agranulocytosis is thought to involve bioactivation to a protein-reactive quinoneimine metabolite. The toxicity of amodiaquine and the lack of cheap drugs have prompted a search for alternative antimalarial agents. The aim of this study was to determine the metabolism and neutrophil toxicity of amodiaquine, pyronaridine, and other related antimalarial agents. Horseradish peroxidase and hydrogen peroxide were used to activate drugs to their respective quinoneimine metabolites. Metabolites were trapped as stable glutathione conjugates, prior to analysis by LC/MS. Amodiaquine was metabolized to a polar metabolite (m/z 661), identified as a glutathione adduct. Tebuquine was converted to two polar metabolites. The principal metabolite (m/z 686) was derived from glutathione conjugation and side chain elimination, while the minor metabolite gave a protonated molecule (m/z 496). Only parent ions were identified when chloroquine, cycloquine, or pyronaridine was incubated with the activating system and glutathione. Calculation of the heat of formation of the drugs, however, demonstrated that amodiaquine, tebuquine, cycloquine, and pyronaridine readily undergo oxidation to their quinoneimine. None of the antimalarial compounds depleted the level of intracellular glutathione (1-300 microM) when incubated with neutrophils alone. Additionally, with the exception of tebuquine, no cytotoxicity below 100 microM was observed. In the presence of the full activating system, however, all compounds except chloroquine resulted in depletion of the level of glutathione and were cytotoxic. Pretreating the cells with glutathione and other antioxidants inhibited metabolism-dependent cytotoxicity. In summary, our data show that amodiaquine and related antimalarials containing a p-aminophenol moiety undergo bioactivation in vitro to chemically reactive and cytotoxic intermediates. In particular, pyronaridine, which is currently being investigated in humans, was metabolized to a compound which was toxic to neutrophils. Thus, the possibility that it will cause agranulocytosis in clinical practice cannot be excluded, and will require careful monitoring.

Effect of Disposition of Mannich Antimalarial Agents on Their Pharmacology and Toxicology

Abstract: The antimalarial agent amodiaquine is effective against both chloroquine-resistant and -sensitive strains of Plasmodium falciparum (24). However, its use has been curtailed due to the development of adverse reactions to the drug during prophylactic administration (7, 11). These drug-induced reactions have been attributed to the ability of amodiaquine to undergo oxidative metabolism to a chemically reactive quinoneimine species, detected in vivo as the excretion of glutathione conjugates in experimental animals (6, 10, 19). Formation of this metabolite requires the presence of a 4-aminophenol group allowing formation of an electrophilic quinoneimine. To date, amodiaquine is unique among antimalarial agents in its ability to form this type of chemically reactive metabolite and to produce idiosyncratic drug reactions in humans. Most toxicities associated with the use of antimalarial agents are related to the dose (9) and have been ascribed to the ability of these compounds to accumulate in acidic cellular lysosomes. However, this mechanism of accumulation has also been proposed as a requirement for the pharmacological activities of some antimalarial agents (4, 8, 30). It has been shown that both the basicity and the lipophilicity have a great influence on the ability of compounds to accumulate (8) and on the site of accumulation (3). The extent of tissue storage is, in turn, known to influence the pharmacokinetics, and tissue distribution plays a major part in the pharmacological profile of a compound with respect to its duration of action, its potency in vivo, and its toxicology. A review of novel and therapeutically used compounds revealed that many antimalarial agents contain a 4-aminophenol group, which may influence their toxicological profiles. These compounds, analogs of amodiaquine, can be classed as Mannich antimalarial agents due to the incorporation of an amine group in their side chains. The introduction of a C-5′-chlorophenyl group (5′-ClPAQ and tebuquine; Fig. ​Fig.1)1) increased the in vivo activity of amodiaquine 20-fold against Plasmodium berghei in the mouse (26). However, neither of these compounds has been used in the clinic. In the case of tebuquine, this was due to chronic toxicity seen during tests with animals, including the appearance of foamy macrophages (25a), a histological finding also seen following the chronic administration of chloroquine to humans (29). Tissue accumulation has been implicated in chloroquine toxicity (9), and the mechanism of tebuquine toxicity may also be a consequence of accumulation. FIG. 1 Chemical structures of amodiaquine and its analogs. Previous studies have shown that bis-Mannich analogs of amodiaquine (cycloquine and bis-pyroquine; Fig. ​Fig.1)1) have higher levels of activity than their mono-Mannich derivatives against both chloroquine-resistant and -sensitive strains of the malarial parasite in vitro (17). In vivo, the activities of bis-Mannich and mono-Mannich compounds are comparable against Plasmodium vinckei vinckei after intraperitoneal (i.p.) administration (1). However, the inclusion of the extra group at the C-5′ position of amodiaquine increases the duration of action for bis-Mannich antimalarial agents. Pyronaridine (Fig. ​(Fig.1),1), a bis-Mannich antimalarial substituted at the C-5′ with a pyrrolidine group and an acridine rather than a quinoline nucleus is currently undergoing clinical trials in China and has already been used effectively in the treatment of resistant strains of P. falciparum both in vitro (17) and in the clinic (20, 27). The aim of this study was to investigate the influence of pharmacokinetics on pharmacodynamics with reference to three types of Mannich antimalarial compounds: the mono-Mannich compound amodiaquine, which has two sites of protonation; 5′-ClPAQ, which contains a chlorophenyl group at C-5′ of amodiaquine and which has a higher level of lipophilicity than amodiaquine; and the bis-Mannich cycloquine, which has three sites of protonation and which has a greater basicity than amodiaquine. These results have been extrapolated to related compounds to see whether physiochemical properties can explain the observed duration of antimalarial activity through changes in the disposition of the compound in vivo.