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Primaquine metabolism

Clark et al. [53] subjected primaquine to metabolic studies using microorganisms. A total of 77 microorganisms were evaluated for their ability to metabolize primaquine, of these, 23 were found to convert primaquine to one or more metabolites (thin-layer chromatography analysis). Preparative scale fermentation of primaquine with four different microorganisms resulted in the isolation of two metabolites, identified as 8-(3-carboxy-l-methylpropylamino)-6-methoxyquinoline and 8-(4-acetamido-l-methylbutylamino)-6-methoxyquinoline. The structures of the metabolites were proposed, based primarily on a comparison of the 13C NMR spectra of the acetamido metabolite and the methyl ester of the carboxy metabolite with that of primaquine. The structures of both metabolites were confirmed by direct comparison with authentic samples. [Pg.182]

Hufford et al [57] used proton and 13C NMR spectrometric data to establish the novel sulfur-containing microbial metabolite of primaquine. Microbial metabolic studies of primaquine using Streptomyces roseochromogenus produced an A-acety-lated metabolite and a methylene-linked dimeric product, both of which have been previously reported, and a novel sulfur-containing microbial metabolite. The structure of the metabolite as an S-linked dimer was proposed on the basis of spectral and chemical data. The molecular formula C34H44N604S was established from field-desorption mass spectroscopy and analytical data. The 1H- and 13C NMR spectra data established that the novel metabolite was a symmetrical substituted dimer of primaquine A-acetate with a sulfur atom linking the two units at carbon 5. The metabolite is a mixture of stereoisomers, which can equilibrate in solution. This observation was confirmed by microbial synthesis of the metabolite from optically active primaquine. [Pg.183]

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. [Pg.198]

Mihaly et al. [128] identified the carboxylic acid derivative of primaquine as a major plasma metabolite. After oral administration of 45 mg of primaquine to healthy volunteers, absorption of the drug was rapid, with peak primaquine levels of 153.3 ng/mL at 3 h, followed by an elimination half-life of 7.1 h, systemic clearance of 21.1 L/h, volume of distribution of 205 L and cumulative urinary excretion of 1.3% of the dose. Primaquine was converted rapidly to the carboxylic acid metabolic, which achieved peak levels of 1427 ng/mL at 7 h. [Pg.198]

Clark et al. [136] studied the excretion, distribution, and metabolism of primaquine in rats. The drug was administered intravenously, intraperitoneally, and orally and blood samples were collected at various time intervals. Primaquine was metabolized by oxidative deamination to give 8-(3-carboxy-l-methylpropylamino)-6-methoxy quinoline. The plasma levels of both primaquine and its metabolites were determined by high performance liquid chromatography. [Pg.200]

Price and Fletcher [139] studied the metabolism and toxicity of primaquine in human and monkeys. Results of a number of studies by the authors on primaquine... [Pg.200]

Hufford et al. [57] used proton and 13C NMR spectrometric data to establish the novel sulfur containing microbial metabolite of primaquine. Microbial metabolic studies of primaquine using S. roseochromogenus produced an A-acctylatcd metabolite and a methylene linked dimeric product, both of which have been previously reported, and a novel sulfur containing microbial metabolite. [Pg.201]

Bangchang et al. [142] studied a number of antimalarial drugs for their effect on the metabolism of primaquine by human liver microsomes (N = 4) in vitro. The only metabolite generated was identified as carboxyprimaquine by cochromatography with the authentic standard. [Pg.201]

Ni et al. [143] investigated the profile of the major metabolites of primaquine produced by in vitro liver microsomal metabolism, with silica gel thin-layer and high performance liquid chromatography analysis. Results indicated that the liver microsomal metabolism could simultaneously produce both 5-hydroxyprimaquine (quinoline ring oxidation product) and carboxyprimaquine (side-chain oxidative deamination product). However, the quantitative comparative study of microsomal metabolism showed that the production of 5-hydroxyprimaquine was far much higher than that of carboxyprimaquine. [Pg.201]

Ni et al. [144] also investigated the profiles of major metabolites of primaquine produced from liver microsomal and mitochondrial metabolism, in vitro by silica gel thin-layer and reversed-phase high performance liquid chromatography. The results... [Pg.201]

Wernsdorfer and Trigg [147] reviewed the pharmacokinetics, metabolism, toxicity, and activity of primaquine. [Pg.202]

Bll. Beutler, E., Drug-induced hemolytic anemia (Primaquine sensitivity). In The Metabolic Basis of Inherited Disease (J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, eds.), pp, 1031-1067. McGraw-Hill, New York, 1960. [Pg.75]

Formation of a lactam as a late metabolite is also possible, as documented by the identification of an important and novel lactam metabolite of the antimalarial drug primaquine (11.148) [161]. When 11.148 was incubated with hamster liver fractions for periods of up to 1 d in the absence of added cofactors, oxidative deamination at both amino groups was the primary metabolic reaction. The metabolite resulting from loss of the primary amino group was further oxidized to the carboxylic acid, which was recovered partly as such and partly as the lactam 11.149. [Pg.739]

Chloroquine is a rapidly acting blood schizonti-cide with some gametocytocidal activity. It is used with primaquine for Plasmodium vivax and Plasmodium ovale infections. It has been widely used prophylactically by traveler s to endemic areas. Its mechanism of action is unclear. It is believed to hinder the metabolism of hemoglobin in the parasite. Presumably chloroquine prevents the formation in the plasmodia of polymers out of free heme which then builds up and becomes toxic. Resistance occurs as a consequence of the expression of a membrane phospho-glycoprotein pump in the plasmodia which is able to expel chloroquine from the parasite. Plasmodium falciparum is the most likely to become resistant. [Pg.425]

Primaquine is readily absorbed from the gastrointestinal tract, and in contrast to chloroquine, it is not bound extensively by tissues. It is rapidly metabolized, and the metabolites are reported to be as active as the parent drug itself. Peak plasma levels are reached in 4 to 6 hours after an oral dose, with almost total drug elimination occurring by 24 hours. The half-life is short, and daily administration is usually required for radical cure and prevention of relapses. [Pg.614]

Genetics In certain individuals, the same dose may produce their effect 5-6 times more among others, which is due to their differing rate of drug metabolism, e.g. haemolysis occurs with primaquine in a person with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. [Pg.41]

Some compounds are stored in the body in specific tissues. Such storage effectively removes the material from circulation and thus decreases the toxicity of the compound. Repeated doses of a toxic substance may be taken up and subsequently stored without apparent toxicity until the storage receptors become saturated then toxicity suddenly occurs. In some cases, the stored compound may be displaced from its storage receptor by another compound that has an affinity for the same receptor. Examples of this phenomenon are the displacement of antidiabetic sul-fonylureas by sulfonamides and the ability of antimalarial drugs such as quina-crine (atabrine) and primaquine to displace each other (Loomis, 1978). A special danger in such cases is that compounds may have escaped detoxifying metabolism while stored in the body, and that their toxicity may be potent and prolonged when released. [Pg.124]

Primaquine phosphate is a synthetic 8-aminoquinoline (Figure 52-2). The drug is well absorbed orally, reaching peak plasma levels in 1-2 hours. The plasma half-life is 3-8 hours. Primaquine is widely distributed to the tissues, but only a small amount is bound there. It is rapidly metabolized and excreted in the urine. Its three major metabolites appear to have less antimalarial activity but more potential for inducing hemolysis than the parent compound. [Pg.1127]

Figure 7.46 The metabolism and toxicity of primaquine. Two metabolites, (1) 6-methoxy-8-hydroxyl am in oqui noline and (2) 5-hydroxyprimaquine, are known to be capable of causing oxidative stress and producing ROS. ROS and the metabolites can be removed by GSH, but when this is depleted, they may damage the red cell cytoskeleton and hemoglobin. Abbreviations ROS, reactive oxygen species GSH, glutathione. Figure 7.46 The metabolism and toxicity of primaquine. Two metabolites, (1) 6-methoxy-8-hydroxyl am in oqui noline and (2) 5-hydroxyprimaquine, are known to be capable of causing oxidative stress and producing ROS. ROS and the metabolites can be removed by GSH, but when this is depleted, they may damage the red cell cytoskeleton and hemoglobin. Abbreviations ROS, reactive oxygen species GSH, glutathione.
Methoxy-8-hydroxylaminoquinoline, an N-hydroxylated metabolite of primaquine (Fig. 7.46), is directly toxic, causing hemolysis and methemoglobinemia in rats. However, there are several pathways of metabolism for primaquine and several potential toxic metabolites. Thus, hydroxylation of primaquine at the 5-position of the quinoline ring also forms redox-active derivatives able to cause oxidative stress within normal and G6PD-deficient human red cells as well as rat erythrocytes (Fig. 7.46). [Pg.344]

PRIMAQUINE H2 RECEPTOR BLOCKERS -CIMETIDINE t efficacy and adverse effects of antimalarials Inhibition of metabolism, some definitely via CYP3A4 Avoid co-administration... [Pg.587]

PRIMAQUINE MEPACRINE t primaquine levels Inhibition of metabolism Warn patients to report the early features of primaquine toxicity (e.g. gastrointestinal disturbance). Monitor FBC closely... [Pg.587]

Primaquine Energy metabolism Differences in the target Trypanosoma spp. [Pg.100]


See other pages where Primaquine metabolism is mentioned: [Pg.201]    [Pg.201]    [Pg.38]    [Pg.187]    [Pg.189]    [Pg.195]    [Pg.200]    [Pg.110]    [Pg.340]    [Pg.400]    [Pg.401]    [Pg.273]    [Pg.194]    [Pg.107]    [Pg.1127]    [Pg.551]    [Pg.158]    [Pg.3]    [Pg.4]    [Pg.158]    [Pg.1019]    [Pg.1724]    [Pg.1591]    [Pg.401]   
See also in sourсe #XX -- [ Pg.329 , Pg.395 ]

See also in sourсe #XX -- [ Pg.78 ]




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Primaquine

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