Studies on the mechanisms of oxidation in the erythrocyte by metabolites of primaquine

Fletcher, K. A.; Pf, Barton; Ja, Kelly

doi:10.1016/0006-2952(88)90263-8

Cited by 70 publications

(50 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most representative hydroxylated metabolite is 5-hydroxyprimaquine (5-HPQ, 8) [146][147][148][149][150][151][152][153]. According to Bowman et al [146], this metabolite induced methemoglobin formation and depletion of glutathione (GSH), when incubated with suspensions of rat erythrocytes.…”

Section: Hydroxylated Speciesmentioning

confidence: 99%

“…Another study evidenced that a double mechanism to oxyhemoglobin oxidation and the reduced glutathione (GSH) occurs by autoxidation of the 5-hydroxy-8-aminoquinolines and their coupled oxidation with oxyhemoglobin [149]. This phenomenon not only applies to 5-HPQ but also to other 5-hydroxylated metabolites such as 5,6-dihydroxyprimaquine (10), 6-methoxy-5-hydroxy-8-aminoquinoline (11) and 5,6-dihydroxy-8-aminoquinoline (12).…”

Section: Hydroxylated Speciesmentioning

confidence: 99%

“…This phenomenon not only applies to 5-HPQ but also to other 5-hydroxylated metabolites such as 5,6-dihydroxyprimaquine (10), 6-methoxy-5-hydroxy-8-aminoquinoline (11) and 5,6-dihydroxy-8-aminoquinoline (12). These oxidative processes yield free radicals, superoxide radical anions, hydrogen peroxide and, ultimately, methemoglobin [149]. The formation of hydrogen peroxide, quinone-imine metabolites, drug-derived free radicals and hydroxyl radicals were demonstrated in another study with 5-HPQ (8), 5,6-dihydroxy-8-aminoquinoline (12) and 5,6-dihydroxyprimaquine (10) [148,150].…”

Section: Hydroxylated Speciesmentioning

confidence: 99%

See 2 more Smart Citations

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

321

308

View full text Add to dashboard Cite

Section: Hydroxylated Speciesmentioning

confidence: 99%

Section: Hydroxylated Speciesmentioning

confidence: 99%

Section: Hydroxylated Speciesmentioning

confidence: 99%

See 1 more Smart Citation

Primaquine revisited six decades after its discovery

Vale¹,

Moreira²,

Gomes³

2009

European Journal of Medicinal Chemistry

321

308

View full text Add to dashboard Cite

“…Primaquine metabolism, on the other hand, is relatively more complex, and the metabolites that mediate the hemotoxic responses have not been identified. A variety of known and putative phenolic metabolites of primaquine are redox-active and therefore have the potential to mediate primaquine hemotoxicity (Strother et al, 1984;Baird et al, 1986;Fletcher et al, 1988;Agarwal et al, 1991); however, direct evidence for their hemolytic activity is lacking. We have recently explored an alternative hypothesis-that primaquine hemotoxicity is mediated by an N-hydroxylated metabolite, 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH).…”

mentioning

confidence: 99%

Primaquine-Induced Hemolytic Anemia: Formation of Free Radicals in Rat Erythrocytes Exposed to 6-Methoxy-8-hydroxylaminoquinoline

Bolchoz

Gelasco

Jollow³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Primaquine is an important antimalarial drug that is often doselimited in therapy by the onset of hemolytic anemia. We have shown recently that an N-hydroxy metabolite of primaquine, 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH), is a directacting hemolytic agent in rat red cells and that the hemolytic activity of this metabolite is associated with GSH oxidation and oxidative damage to both membrane lipids and skeletal proteins. To determine whether the formation of free radicals may be involved in this process, rat red cells (40% suspensions) were incubated with hemolytic concentrations of MAQ-NOH (150 -750 M) and examined by EPR spectroscopy using 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide (EMPO) as a spin trap. Addition of MAQ-NOH to red cell suspensions containing 10 mM EMPO gave rise to an EPR spectrum with hyperfine constants consistent with those of an EMPO-hydroxyl radical adduct standard. Of interest, formation of EMPO-OH was constant for up to 20 min and dependent on the presence of erythrocytic GSH. Although no other radical adduct signals were detected in the cells by EPR, spectrophotometric analysis revealed the presence of ferrylhemoglobin, which indicates that hydrogen peroxide is generated under these experimental conditions. The data support the hypothesis that oxygen-derived and possibly other free radicals are involved in the mechanism underlying MAQ-NOH-induced hemolytic anemia.Hemolytic anemia and methemoglobinemia are well recognized dose-limiting side effects in the therapeutic use of arylamine drugs, such as primaquine and dapsone (Beutler, 1969). Because these compounds are not hemotoxic when incubated with red cells in vitro, it has long been appreciated that metabolites are responsible for the onset of the hemolytic response. In the cases of aniline (Harrison and Jollow, 1986), dapsone (Grossman and Jollow, 1988), and phenacetin (Jensen and Jollow, 1991), we have shown that the hemolytic metabolites are their N-hydroxy derivatives. Primaquine metabolism, on the other hand, is relatively more complex, and the metabolites that mediate the hemotoxic responses have not been identified. A variety of known and putative phenolic metabolites of primaquine are redox-active and therefore have the potential to mediate primaquine hemotoxicity (Strother et al., 1984;Baird et al., 1986;Fletcher et al., 1988;Agarwal et al., 1991); however, direct evidence for their hemolytic activity is lacking. We have recently explored an alternative hypothesis-that primaquine hemotoxicity is mediated by an N-hydroxylated metabolite, 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH).Although the mechanism underlying the damage and removal of red cells by hemolytic N-hydroxylamines remains unclear, oxidative stress has long been considered to play a prominent role in the process (for review, see Beutler, 1971). This concept is based on the well known association of hemotoxicity with oxidation of erythrocytic GSH (to glutathione disulfide and glutathione protein-mixed disulfides), with methemoglobin f...

show abstract

“…P. vivax, in contrast to P. falciparum infection does not significantly influence the disposition of PQ (Edwards et al, 1993;Cuong et al,2006;Elmes et al, 2006). PQ and several of its metabolites, 5-hydroxydemethylprimaquine, 5-hydroxyprimaquine and demethylprimaquine have been shown to cause red cell lysis in vitro (Fletcher et al, 1988). The serious hemolytic effect of PQ is of great concern especially with conconcurrent pharmacokinetic drug interactions that could aggravate the effect.…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 99%

A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

Chukanchitipat¹,

Na‐Bangchang²

2017

Afr. J. Pharm. Pharmacol.

View full text Add to dashboard Cite

The blood schizontocidal chloroquine (CQ) and the tissue schizontocidal and gametocytocidal primaquine (PQ) remain the mainstay treatment of Plasmodium vivax and Plasmodium ovale infections for more than six decades. The review focuses on the clinical pharmacokinetic studies of both drugs in Thai population that have provided useful information for clinical application in the treatment of malaria. There appears to be no major differences in the pharmacokinetics of both drugs with respect to the influences of ethinicity, acute phase malaria infection, and G6PD status. The increase in systemic exposure of CQ and/or its metabolite mono-desethylchlorooquine (DECQ) following oral administration could be due to change in the absorption kinetics during acute phase infection. The high clinical efficacy of CQ for treatment of P. vivax infection in Thailand supports this benefitial pharmacokinetic change. Transiently high and toxic plasma/whole blood concentrations of CQ following intravenous infusion at high rate is explained by the pharmacokinetic characteristics of CQ. Pharmacokinetics of PQ following repeated dosing in most studies appears to be similar to that following a single dosing. This suggests that auto-inhibition of PQ metabolism during multiple dosing is unlikely. Coadministration of CQ, dihydroartemisinin-piperaquine (DHA-PIP), and pyronaridine-artesunate (PYR-ARS) significantly altered the pharmacokinetics of PQ. In the presence of these drugs, PQ exposure was significantly increased. The apparent volume of distribution of PQ was reduced when coadministered with PYR-ARS. In addition, plasma concentrations of CPQ were significantly increased in the presence of CQ. Clinical relevance of these interactions needs to be confirmed.

show abstract

Studies on the mechanisms of oxidation in the erythrocyte by metabolites of primaquine

Cited by 70 publications

References 16 publications

Primaquine revisited six decades after its discovery

Primaquine revisited six decades after its discovery

Primaquine-Induced Hemolytic Anemia: Formation of Free Radicals in Rat Erythrocytes Exposed to 6-Methoxy-8-hydroxylaminoquinoline

A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

Contact Info

Product

Resources

About