Metabolism of chloroquine and hydroxychloroquine in albino and pigmented rats

McChesney, Evan W.; Banks, W. F.; Sullivan, David J.

doi:10.1016/0041-008x(65)90050-5

Cited by 57 publications

(27 citation statements)

References 14 publications

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“…To evaluate the feasibility of measuring exogenous compounds and metabolite concentrations directly from tissue sections, a drug with well‐known pharmacokinetics and metabolite profile i.e. CHQ), was selected . CHQ has a very large volume of distribution and has been associated with renal toxicity .…”

Section: Resultsmentioning

confidence: 99%

Analysis of chloroquine and metabolites directly from whole‐body animal tissue sections by liquid extraction surface analysis (LESA) and tandem mass spectrometry

et al. 2012

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The rapid and direct analysis of the amount and spatial distribution of exogenous chloroquine (CHQ) and CHQ metabolites from tissue sections by liquid extraction surface sampling analysis coupled with tandem mass spectrometry (LESA-MS/MS) was demonstrated. LESA-MS/MS results compared well with previously published CHQ quantification data collected by organ excision, extraction and fluorescent detection. The ability to directly sample and analyze spatially resolved exogenous molecules from tissue sections with minimal sample preparation and analytical method development has the potential to facilitate the assessment of target tissue penetration of pharmaceutical compounds, to establish pharmacokinetic/pharmacodynamic relationships, and to complement established pharmacokinetic methods used in the drug discovery process during tissue distribution assessment.

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Section: Resultsmentioning

confidence: 99%

Analysis of chloroquine and metabolites directly from whole‐body animal tissue sections by liquid extraction surface analysis (LESA) and tandem mass spectrometry

et al. 2012

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“…The results of McChesney et al (1965) showed chloroquine tissue concentration to fall by over 70% in 9 days and by over 90% in 15 days on stopping the drug. This rapid fall in tissue concentration might contribute to the failure to observe tissue saturation in our study in which the drug was administered weekly and tissue specimens were taken 7 days after a dose.…”

Section: Discussionmentioning

confidence: 96%

Tissue and blood concentrations of chloroquine following chronic administration in the rat

Adelusi

Salako

1982

Journal of Pharmacy and Pharmacology

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The antimalarial drug, chloroquine, is extensively distributed in tissue and slowly eliminated such that after a single dose, a plasma half-life of 3-5 days has been found (McChesney & McAuliff 1961; McChesney et al 1967). A peak tissue/plasma concentration ratio greater than 300 is obtained in many tissues and after a single dose the drug can be found in the liver and urine for up to five years (Gaudette & Coatney 1961; Rubin et al 1963; Zvaifler et al 1963). Chronic administration of chloroquine for the treatment of rheumatoid arthritis has revealed an ocular toxicity due to accumulation of the drug in the pigmented layers of the eye, particularly the choroid (Fuld & Horwish 1958; Fuld 1959). A more recent indication for chronic administration of chloroquine is in the prophylaxis of malaria, for which the drug is administered at a dose of 300-600 mg weekly to adults. The long term toxic effects of chloroquine when administered in this way are unknown but no ocular toxicity has been reported even after five years of such use. Since tissue toxicity and other untoward effects are largely determined by tissue stores (Fuld & Horwish 1958; Fuld 1959) and blood levels (Laaksonen et al 1974; Frisk-Holmberg et al 1979) of the drug, it is useful to know the changes occurring in tissue and plasma concentrations during chronic administration. Previous studies in animals have given conflicting results. McChesney et al (1965) found a steady increase in the tissue and plasma concentrations in rats throughout a 3-month period although the increase was fastest in the first month. Grundmann et al (1972) found that most rat tissues were saturated with chloroquine between the 10th and the 16th weeks. Plasma concentrations were not measured hence the effect of tissue saturation on blood levels was not determined, yet saturation of tissue stores would be expected to lead to a rapid increase in plasma concentration that could affect the pattern and incidence of adverse reactions to the drug. We have reinvestigated the uptake of chloroquine by rat tissues during chronic administration of the drug and in particular to relate the tissue levels to plasma concentrations.

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“…The metabolism of CQ and HCQ to desethyl and other metabolites has been extensively studied in rats and humans (McChesney et al 1965(McChesney et al , 1966(McChesney et al , 1967aMcChesney 1983;McChesney and Fitch 1984;Furst 1996). CQ and HCQ are rapidly dealkylated by cytochrome P 450 enzymes (CYP) to pharmacological active desethyl (DE-CQ) and bis-desethyl CQ (BDE-CQ) in the case of CQ, and the monohydroxyl HCQ (M-HCQ) and desethyl HCQ (D-HCQ) in case of HCQ (McChesney 1983;McChesney and Fitch 1984;Furst 1996;Spaldin et al 1994; Metabolic pathways of racemic chloroquine as determined from the urinary excretion over 24 h of the drug and metabolites determined by gas chromatography-mass spectrometry following intake by 5 volunteers of 250 mg chloroquine diphosphate (=150 mg chloroquine base).…”

Section: Cytochromes P450mentioning

confidence: 99%

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases

et al. 2015

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HCQ and CQ have a good reputation for being effective and relatively safe treatments in SLE, mild-moderate RA and Sjøgren's syndrome. There is need for (a) more information on their mode of action in relation to the control of these diseases, (b) scope for developing formulations that have improved pharmacokinetic and therapeutic properties and safety, and (c) further exploring their use in drug combinations not only with other disease modifying agents but also with biologics.

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Metabolism of chloroquine and hydroxychloroquine in albino and pigmented rats

Cited by 57 publications

References 14 publications

Analysis of chloroquine and metabolites directly from whole‐body animal tissue sections by liquid extraction surface analysis (LESA) and tandem mass spectrometry

Analysis of chloroquine and metabolites directly from whole‐body animal tissue sections by liquid extraction surface analysis (LESA) and tandem mass spectrometry

Tissue and blood concentrations of chloroquine following chronic administration in the rat

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases

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