The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects

Frisk-Holmberg, M; Bergqvist, Yngve; Termond, E. F. S.; Domeij-Nyberg, B

doi:10.1007/bf00542151

Cited by 122 publications

(103 citation statements)

References 15 publications

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“…The various rate constants are apparently independent of dose (Frisk-Holmberg et al, 1984). Thus, when a minimal dose of drug is injected (e. g., insufficient for radical cure), as done in the present work, it is not unlikely that the peak drug concentrations prevail for a period that is sufficient to kill the most sensitive stage.…”

Section: G Cambie and Collaboratorsmentioning

confidence: 71%

“…It is therefore not surprizing that various drugs were found to exert differen tial effects on the distinct stages of parasite maturation (Yayon et al, 1983;Dieckman and Jung, 1986;Geary et al, 1989). These considerations, in conjunction with the pharmacokinetics of antimalarial drugs (Frisk-Holmberg et al, 1984;Aderounmu et al, 1987;White et al, 1987), call for the contemplation of a chronotherapeutic approach to the treatment of malaria.…”

Section: Résumé : Chronothérapie Du Paludisme : Identification Du Stamentioning

confidence: 99%

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Chronotherapy of malaria: identification of drug-sensitive stage of parasite and timing of drug delivery for improved therapy

Cambiè¹,

Caillard

Beauté-Lafitte

et al. 1991

Ann. Parasitol. Hum. Comp.

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The cyclic nature of malarial fever in conjunction with the phar macokinetic characteristics of antimalarial drugs, call for the conception of a chronotherapeutic approach for the treatment of the disease. An experimental murine malarial model was devised using the highly synchronous species Plasmodium vinckei petteri to test this rationale. Sub-curative doses of chloroquine were injected sub-cutaneously to mice either during the prepatent period or during patent infection. Inspection of the effet of drug applied at different stages of the parasitic cycle, revealed that medium size trophozoites (MT) were the most susceptible stage to chloro quine, while ring and young trophozoite stages were refractory to the drug. Chloroquine given during these latter stages, affected the parasites when they developed into the MT stage. Drug treat ment during the MT stage phase-shifted the schizogonic cycle by 18 hours. Hence, treatment with two consecutive injections given 18 hours apart, i. e. timed to the overwhelming presence of the MT stage in the circulation, gave the best therapeutic results. Résumé : Chronothérapie du paludisme : identification du stade sensible du parasite et horaires du traitement permettant d'améliorer son efficacité.Le caractère cyclique des accès de paludisme et les particularités pharmacocinétiques des médicaments antipaludiques permettent une approche chronothérapique du traitement de la maladie. Pour éprouver cette hypothèse, un modèle expérimental murin a été mis au point avec l'espèce hautement synchrone, Plasmodium vinckei petteri. Des doses sub-curatives de chloroquine sont injec tées à des Souris, par voie sous-cutanée soit pendant la période pré-patente soit au cours des infections patentes. L'étude de l'effet du médicament administré sur différents stades du cycle érythro cytaire a montré que le trophozoite moyen était le stade le plus

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Section: G Cambie and Collaboratorsmentioning

confidence: 71%

Section: Résumé : Chronothérapie Du Paludisme : Identification Du Stamentioning

confidence: 99%

Chronotherapy of malaria: identification of drug-sensitive stage of parasite and timing of drug delivery for improved therapy

Cambiè¹,

Caillard

Beauté-Lafitte

et al. 1991

Ann. Parasitol. Hum. Comp.

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“…The in vitro activity of the primary amine against both chloroquine-susceptible and chloroquine-resistant strains was very low (16). In contrast, after oral administration of chloroquine the concentrations of mono-and bidesethyl chloroquine reached about 1/3 to 2/3 and 1/50 that of chloroquine, respectively (7,19). When amodiaquine is given orally, relatively small amounts of the parent drug are present in blood (23).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria

Verdier

Pussard

Clavier

et al. 1989

Antimicrob Agents Chemother

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The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 + 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 + 75 liters/kg and 2,063 ± 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 + 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.The 4-amino quinoline amopyroquin was proposed for antimalarial therapy nearly 30 years ago. It has been effective in the treatment of acute Plasmodium falciparum and Plasmodium vivax malaria (10,11,17). Moreover, amopyroquin seems more active in vitro than the other 4-amino quinolines (chloroquine or monodesethyl amodiaquine) against resistant strains of P. falciparum (15).Amopyroquin is metabolized more extensively in rats than in rabbits to three metabolites, one of which is probably the primary amine derivative (15). In rats, amopyroquin is widely distributed in tissues and in plasma the drug concentrations are decreased, with a terminal half-life of 14 h (15,18). But during the 8 h after a single 60-or 120-mg/kg (body weight) dose of amopyroquin given intraperitoneally, this half-life has been estimated as 2 h (6). In rabbits, a similar bioavailability, about 70%, was observed after oral and intramuscular (i.m.) administration, and terminal elimination half-lives were 18, 24, and 26 h for intravenous (i.v.), i.m., and oral routes, respectively (15). No study has described the metabolism and the pharmacokinetic behavior of amopyroquin in humans.The aims of the present study were as follows: (i) to investigate the metabolism and the pharmacokinetic parameters of amopyroquin in healthy subjects after i.m. administration of amopyroquin base at 2 mg/kg (body weight) and (ii) to compare the following three i.m. therapeutic regimens in P. falciparum malaria patients on the basis of drug concentrations in the blood and in vivo efficacy: 3 mg/kg (body weight) (group 1), 6 mg/kg (group 2), and 6 mg/kg followed by 3 mg/kg 24 h later (group 3). * Corresponding...

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“…The decline in plasma concentrations after a single dose is multiphasic with an extremely long terminal elimination phase during which plasma concentrations are measurable for up to three months (Gustafsson et al, 1983;Frisk-Holmberg et al, 1984 The enormous differences between these values, and between the distribution and elimination phase rate constants mean that the plasma concentration profile and toxicity of parenteral chloroquine during the usual 3 day treatment course in falciparum malaria, would be determined largely by distribution rather than elimination processes.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular toxicity and distribution kinetics of intravenous chloroquine.

White¹,

Chanthavanich²,

Edwards³

et al. 1986

Brit J Clinical Pharma

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1 Chloroquine diphosphate (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations.2 Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml-'. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+ s.d.) first order rate constant 0.65 + 0.14 min7t, and an estimated apparent volume of the central compartment of 0.18 + 0.15 1 kg-1. 3 There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 + 9.5 to 101 ± 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. 4 Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 + 15 to 92 + 13 ms (P < 0.01) but no change in the QTc interval. 5 These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity.

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The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects

Cited by 122 publications

References 15 publications

Chronotherapy of malaria: identification of drug-sensitive stage of parasite and timing of drug delivery for improved therapy

Chronotherapy of malaria: identification of drug-sensitive stage of parasite and timing of drug delivery for improved therapy

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria

Cardiovascular toxicity and distribution kinetics of intravenous chloroquine.

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