Pharmacokinetics of Chloroquine and Some of Its Metabolites in Healthy Volunteers: A Single Dose Study

Ette, Ene I.; Essien, Emmanuel E.; Thomas, W. O. A.; Brown-Awala, Esther A.

doi:10.1002/j.1552-4604.1989.tb03362.x

Cited by 32 publications

(20 citation statements)

References 12 publications

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“…Accordingly, the finding that, in humans, DCQ was readily detectable in plasma during the absorption phase of CQ pointed to an enzymatic system with a high capacity (Ducharme and Farinotti, 1996). The predicted nonrenal clearance value of 0.52 Ϯ 0.04 ml/min/kg estimated from the present HLM investigations is in agreement with the one obtained in vivo from normal subjects (0.63-1.02 ml/min/kg; Frisk-Holmberg et al, 1983;Gustafsson et al, 1983;Ette et al, 1989).…”

Section: Chloroquine N-desethylation By Cyp2c8 Cyp3a4 and Cyp2d6supporting

confidence: 87%

“…In vivo, the formation rates of DCQ and BDCQ, from CQ and DCQ, respectively, are strongly correlated (r ϭ 0.83) (Ette et al, 1989). In vitro, in HLM, our study demonstrated that DCQ is N-desethylated into BDCQ via an NADPH-dependent system.…”

Section: Chloroquine N-desethylation By Cyp2c8 Cyp3a4 and Cyp2d6supporting

confidence: 52%

“…In humans, the liver and kidneys contribute approximately equally to its body disposition (Frisk-Holmberg et al, 1983;Gustafsson et al, 1983;Ette et al, 1989). Following oral or i.v.…”

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confidence: 99%

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IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

Projean

Baune²,

Farinotti³

et al. 2003

Drug Metab Dispos

164

117

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ABSTRACT:In humans, the antimalarial drug chloroquine (CQ) is metabolized into one major metabolite, N-desethylchloroquine (DCQ). Using human liver microsomes (HLM) and recombinant human cytochrome P450 (P450), we performed studies to identify the P450 isoform(s) involved in the N-desethylation of CQ. In HLM incubated with CQ, only DCQ could be detected. Apparent K m and V max values (mean ؎ S.D.) for metabolite formation were 444 ؎ 121 M and 617 ؎ 128 pmol/min/mg protein, respectively. In microsomes from a panel of 16 human livers phenotyped for 10 different P450 isoforms, DCQ formation was highly correlated with testosterone 6␤-hydroxylation (r ‫؍‬ 0.80; p < 0.001), a CYP3A-mediated reaction, and CYP2C8-mediated paclitaxel ␣-hydroxylation (r ‫؍‬ 0.82; p < 0.001). CQ N-desethylation was diminished when coincubated with quercetin (20-40% inhibition), ketoconazole, or troleandomycin (20-30% inhibition) and was strongly inhibited (80% inhibition) by a combination of ketoconazole and quercetin, which further corroborates the contribution of CYP2C8 and CYP3As. Of 10 cDNAexpressed human P450s examined, only CYP1A1, CYP2D6, CYP3A4, and CYP2C8 produced DCQ. CYP2C8 and CYP3A4 constituted low-affinity/high-capacity systems, whereas CYP2D6 was associated with higher affinity but a significantly lower capacity. This property may explain the ability of CQ to inhibit CYP2D6-mediated metabolism in vitro and in vivo. At therapeutically relevant concentrations (ϳ100 M CQ in the liver), CYP2C8, CYP3A4, and, to a much lesser extent, CYP2D6 are expected to account for most of the CQ N-desethylation.

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Section: Chloroquine N-desethylation By Cyp2c8 Cyp3a4 and Cyp2d6supporting

confidence: 87%

Section: Chloroquine N-desethylation By Cyp2c8 Cyp3a4 and Cyp2d6supporting

confidence: 52%

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IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

Projean

Baune²,

Farinotti³

et al. 2003

Drug Metab Dispos

164

117

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“…To enable simultaneous modeling of CQ and DECQ data sets, we fixed the metabolic conversion ratio using published data (11). A limitation of this approach is that BSV contained in CL M /F cannot be assessed, but it becomes a component of a The numbers in parentheses represent the simulated medians for pregnant subjects expressed as percentages of that for the standard dose of 3 tablets (450 mg CQ base) in 3 daily doses for nonpregnant subjects.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Chloroquine and Monodesethylchloroquine in Pregnancy

Karunajeewa

Salman

Müeller

et al. 2010

Antimicrob Agents Chemother

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In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metabolite, desethylchloroquine (DECQ), when administered as intermittent presumptive treatment in pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were administered three daily doses of 450 mg CQ (8.5 mg/kg of body weight/day) in addition to a single dose of sulfadoxine-pyrimethamine. For all women, blood was taken at baseline; at 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h posttreatment; and at 7, 10, 14, 28, and 42 days posttreatment. Plasma was subsequently assayed for CQ and DECQ by high-performance liquid chromatography, and population pharmacokinetic modeling was performed. Pregnant subjects had significantly lower area under the plasma concentration-time curve for both CQ (35,750 versus 47,892 g ⅐ h/liter, P < 0.001) and DECQ (23,073 versus 41,584 g ⅐ h/liter, P < 0.001), reflecting significant differences in elimination half-lives and in volumes of distribution and clearances relative to bioavailability. Reduced plasma concentrations of both CQ and DECQ could compromise both curative efficacy and posttreatment prophylactic properties in pregnant patients. Higher IPTp CQ doses may be desirable but could increase the risk of adverse hemodynamic effects.There are few affordable antimalarial drugs that can be used safely in pregnancy. The efficacy of one of these, chloroquine (CQ), has been compromised by the widespread development of Plasmodium falciparum resistance. However, due to a lack of suitable alternatives, CQ is still widely used in pregnant women, either alone or in combination with other drugs such as sulfadoxine-pyrimethamine (SP), while it remains the drug of choice for Plasmodium vivax in most countries (13,21,34). Although the physiologic changes of pregnancy can alter drug disposition through increased plasma volume, increased clearance, and altered protein binding (15), there have been only three relatively small published studies of CQ pharmacokinetics, from which only limited conclusions can be drawn (9,21,23).Detailed antimalarial pharmacokinetic studies of pregnant women have been identified as an urgent priority, both for optimization of acute treatment and development of new intervention strategies such as intermittent preventive treatment in pregnancy (IPTp) (29). We have, therefore, assessed CQ disposition in pregnant Papua New Guinean (PNG) women and a matched group of nonpregnant female controls. In order to maximize the clinical relevance of our data, we utilized a long (42-day) sampling period (32), measured simultaneous plasma concentrations of the active metabolite of CQ, desethylchloroquine (DECQ) (6), and incorporated both CQ and DECQ in the development of pharmacokinetic models. MATERIALS AND METHODSStudy site and sample. The present study was conducted at Alexishafen Health Centre, Madang Province, between February and July 2006. Eligibility criteria and the characteristics of the 30 pregnant and 3...

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“…The method was partially validated in human plasma. It can be used for estimation of chloroquine in human plasma from clinical studies and measuring residual chloroquine levels in volunteers/patients being enrolled for new antimalarial drug trials, as chloroquine has long half-life of 106.43 ± 10.13 h [35]. …”

Section: Applicationmentioning

confidence: 99%

Sensitive and rapid liquid chromatography/tandem mass spectrometric assay for the quantification of chloroquine in dog plasma

Singhal¹,

Gaur²,

Behl³

et al. 2007

Journal of Chromatography B

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A simple, sensitive and rapid liquid chromatography/tandem mass spectrometric (LC-MS/MS) method was developed and validated for quantification of chloroquine, an antimalarial drug, in plasma using its structural analogue, piperazine bis chloroquinoline as internal standard (IS). The method is based on simple protein precipitation with methanol followed by a rapid isocratic elution with 10 mM ammonium acetate buffer/methanol (25/75, v/v, pH 4.6) on Chromolith SpeedROD RP-18e reversed phase chromatographic column and subsequent analysis by mass spectrometry in the multiple reaction monitoring mode (MRM). The precursor to product ion transitions of m/z 320.3-->247.2 and m/z 409.1-->205.2 were used to measure the analyte and the IS, respectively. The assay exhibited a linear dynamic range of 2.0-489.1 ng/mL for chloroquine in dog plasma. The limit of detection (LOD) and lower limit of quantification (LLOQ) were 0.4 and 2.0 ng/mL, respectively in 0.05 mL plasma. Acceptable precision and accuracy were obtained for concentrations over the standard curve range of 2.0-489.1 ng/mL. A run time of 2.0 min for a sample made it possible to achieve a throughput of more than 400 plasma samples analyzed per day. The validated method was successfully used to analyze samples of dog plasma during non-clinical study of chloroquine.

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Pharmacokinetics of Chloroquine and Some of Its Metabolites in Healthy Volunteers: A Single Dose Study

Cited by 32 publications

References 12 publications

IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZINGN-DESETHYLCHLOROQUINE FORMATION

Pharmacokinetics of Chloroquine and Monodesethylchloroquine in Pregnancy

Sensitive and rapid liquid chromatography/tandem mass spectrometric assay for the quantification of chloroquine in dog plasma

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