Desethylchloroquine Concentrations Research Articles

Genotype-guided new approach for dose optimisation of hydroxychloroquine administration in Chinese patients with SLE

ObjectivesThe study aims to investigate the impact of gene polymorphisms on blood hydroxychloroquine (HCQ) concentrations in patients with SLE and provide guidelines for individualised care.Methods489 Chinese patients with SLE taking...

Resistance of infection by Plasmodium vivax to chloroquine in Bolivia.

BackgroundChloroquine (CQ) over three days plus primaquine (PQ) for seven days is the treatment of choice of infections by Plasmodium vivax in Bolivia, where 95% of the cases of malaria are attributed to this species. The aim of this study was to evaluate the therapeutic efficacy of CQ in this setting.MethodsPatients in the Amazon region of northern Bolivia, were included in the study from May to November 2011 and the therapeutic efficacy of CQ was evaluated over a 28-day follow-up period. Patients with P. vivax mono-infection received 25 mg/Kg body weight of CQ over three days. The concentrations of CQ + desethylchloroquine (DCQ) in blood were determined at days 7 and 28 of follow up; at follow-up and on the day of treatment failure was administered PQ.ResultsOne hundred patients fulfilled the inclusion criteria, two were lost to follow up and another two were later excluded for protocol violation. Of the 96 patients who completed the follow up 10 showed TF; one presented continued parasitaemia until day 7 of follow up, three on day 21 and six on day 28 of follow up. The geometric mean of CQ + DCQ on day 7 was 321.7 ng/ml (range 197–535 ng/ml). In six patients with TF the CQ + DCQ concentrations in blood on the day of TF were >100 ng/ml. The rate of resistance was 6.5%.ConclusionThe present study demonstrates the presence of resistance to CQ in the treatment of malaria by P. vivax in the Amazon region of Bolivia. New clinical trials are needed to establish alternative treatments against these parasites in this region of South America.

FRI0441 Risk factors of chloroquine maculopathy and role of plasma chloroquine and desethylchloroquine concentrations in predicting chloroquine maculopathy

ObjectivesTo investigate the risk factors for chloroquine maculopathy (CM), and to explore factors associated with plasma chloroquine (CQ) and desethylchloroquine (DCQ) levels.MethodsTwo-hundred and thirty-three rheumatoid arthritis (RA) patients who had...

Prevalence and risk factors for chloroquine maculopathy and role of plasma chloroquine and desethylchloroquine concentrations in predicting chloroquine maculopathy

To determine the prevalence and to identify the risk factors of chloroquine maculopathy (CM), and to evaluate the association of plasma chloroquine (CQ) and desethylchloroquine (DCQ) levels and CM. Rheumatoid arthritis (RA) patients who had taken CQ for at least 6months and stable CQ dosage for at least 2months were included. CM was diagnosed by dilated ocular examination and automated visual field. Plasma CQ and DCQ levels were determined by liquid chromatography tandem mass spectrometry method. Logistic regression was used to explore risk factors associated with CM. One hundred and ninety-three patients were included with median CQ duration (range) of 50.2months (6.0-269.8) and cumulative dose of 137.4g (16.4-1226.5). The prevalence of CM was 13.5%. Factors associated with CM identified from univariate analysis were age>60years, and creatinine clearance with odds ratio (OR) (95%CI) of 5.79 (2.42, 13.84), and 0.98 (0.96, 1.00). In multivariate analysis, older age, usage>5years, and current dose from 2.5mg/kg ideal body weight [IBW]/day were the factors significantly associated with CM with OR of 5.89 (2.38, 14.57), 2.94 (1.10, 7.83), and 3.32 (1.04, 10.60), respectively, while plasma CQ and DCQ showed no association with CM. The prevalence of CM was 13.5% among RA patients taking CQ for at least 6months. Age>60years, duration of CQ usage>5years and current CQ dose ≥2.5mg/kg IBW/day were the risk factors for CM. The plasma CQ or DCQ levels demonstrated no correlation in developing CM.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).

BackgroundTafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns.MethodsIn 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans.ResultsThe total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies.ConclusionsTen-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.

Relationship between blood hydroxychloroquine and desethylchloroquine concentrations and cigarette smoking in treated patients with connective tissue diseases

Cigarette smoking has been suspected to increase the risk and the activity of systemic lupus erythematosus (SLE)1 2 and cutaneous lupus.3 4 Some data indicate that cigarette smoking might interfere...

Chloroquine-resistant Plasmodium malariae in south Sumatra, Indonesia

Oral chloroquine is the treatment of choice for uncomplicated Plasmodium malariae infections worldwide. We did a prospective 28-day in-vivo assessment of the efficacy of chloroquine for treatment of P malariae on Legundi Island in Lampung Bay, Sumatra, Indonesia. Of 28 patients, one had recurrent parasitaemia on day 28, and two had persistent parasitaemia to day 8. Whole-blood chloroquine and desethylchloroquine concentrations were at ordinarily effective levels (> or = 100 microg/L) on day 8 in both cases of persistent parasitaemia. These findings suggest that clinical resistance to chloroquine by P malariae occurs in the Indonesian archipelago of southeast Asia.

Chloroquine and desethylchloroquine concentrations in blood cells and plasma from Indian patients infected with sensitive or resistant Plasmodium falciparum.

The sensitivities of 61 Indian cases of Plasmodium falciparum malaria to chloroquine (CQ) were investigated using in-vitro and in-vivo methods. Concentrations of CQ and desethylchloroquine (DCQ) in blood cells and plasma from CQ-sensitive and -resistant cases were determined 2 and 7 days after initiation of treatment, by HPLC. On day 2, the mean CQ concentrations in the samples collected from the sensitive cases were higher than those in the samples from the resistant patients, in plasma (0.47 v. 0.32 microgram/ml; P < 0.02) and particularly in the blood cells (1.51 v. 0.46 micrograms/ml; P < 0.001). By day 7, however, the CQ concentrations in the two groups were similar. Although, on day 2, the mean ratio of the CQ to DCQ concentrations was significantly higher in the blood cells from the sensitive group than in those from the resistant cases (P < 0.01), the CQ/DCQ ratios for the plasma were similar for the two groups. Similarly, the mean ratio between the blood-cell concentration of CQ on day 2 and the concurrent plasma concentration (BPr) was also relatively high in the sensitive group (P < 0.001).

Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements.

This paper presents the current state of knowledge on chloroquine disposition, with special emphasis on stereoselectivity and microsomal metabolism. In addition, the impact of the patient's physiopathological status and ethnic origin on chloroquine pharmacokinetics is discussed. In humans, chloroquine concentrations decline multiexponentially. The drug is extensively distributed, with a volume of distribution of 200 to 800 L/kg when calculated from plasma concentrations and 200 L/kg when estimated from whole blood data (concentrations being 5 to 10 times higher). Chloroquine is 60% bound to plasma proteins and equally cleared by the kidney and liver. Following administration chloroquine is rapidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmacologically active desethylchloroquine and bisdesethylchloroquine. Desethylchloroquine and bisdesethylchloroquine concentrations reach 40 and 10% of chloroquine concentrations, respectively; both chloroquine and desethylchloroquine concentrations decline slowly, with elimination half-lives of 20 to 60 days. Both parent drug and metabolite can be detected in urine months after a single dose. In vitro and in vivo, chloroquine and desethylchloroquine competitively inhibit CYP2D1/6-mediated reactions. Limited in vitro studies and preliminary data from clinical experiments and observations point to CYP3A and CYP2D6 as the 2 major isoforms affected by or involved in chloroquine metabolism. In vitro efficacy studies did not detect any difference in potency between chloroquine enantiomers but, in vivo in rats, S(+)-chloroquine had a lower dose that elicited 50% of the maximal effect (ED950) than that of R(-)-chloroquine. Stereoselectivity in chloroquine body disposition could be responsible for this discrepancy. Chloroquine binding to plasma proteins is stereoselective, favouring S(+)-chloroquine (67% vs 35% for the R-enantiomer). Hence, unbound plasma concentrations are higher for R(-)-chloroquine. Following separate administration of the individual enantiomers, R(-)-chloroquine reached higher and more sustained blood concentrations. The shorter half-life of S(+)-chloroquine appears secondary to its faster clearance. Blood concentrations of the S(+)-forms of desethylchloroquine always exceeded those of the R(-)-forms, pointing to a preferential metabolism of S(+)-chloroquine.

Chloroquine levels in blood during chronic treatment of patients with rheumatoid arthritis.

Blood levels of racemic chloroquine and its main metabolites desethylchloroquine and bisdesethylchloroquine were measured in 29 patients treated chronically for rheumatoid arthritis. In six patients, the concentrations were followed during a one day dosage interval. There was considerable intersubject variability in the steady state blood concentrations of chloroquine (range 36.6 to 3895 ng.ml-1) and its two main biotransformation products; the latter represented, respectively, 47.7% and 12.9% of the concentration of chloroquine. This finding shows the need for further studies in view of the known toxic effects of chloroquine and the inevitable accumulation due to the exceptionally long residence time of the compound and its metabolites. The main requirement, which has not yet been met, for adding chloroquine to the list of drugs for which therapeutic drug monitoring is useful, is the lack of information about its mechanism of action, and consequently the dose-effect relationships of its therapeutic and toxic actions. Regular ophthalmic examination, in particular, is strongly recommended. The relatively high concentrations of desethylchloroquine and bisdesethylchloroquine found during chronic treatment show the need for more information about the therapeutic value and adverse effects of the metabolites.

Single dose disposition of chloroquine in kwashiorkor and normal children‐evidence for decreased absorption in kwashiorkor.

The single dose disposition of chloroquine was studied in five children with kwashiorkor and six normal control children after an oral dose of 10 mg kg-1 of chloroquine base. Plasma concentrations of chloroquine and its main metabolite were assayed by high performance liquid chromatography (h.p.l.c.). Chloroquine was detectable for up to 21 days in all the subjects. Chloroquine was detectable in all the subjects within 30 min after giving the drug except in one subject. Peak levels were reached between 0.5 and 8 h in all the subjects (with no significant difference in the tmax between the two groups of children). Peak plasma chloroquine concentrations in the children with kwashiorkor varied from 9 ng ml-1 to 95 ng ml-1 (mean 40 +/- 34 ng ml-1). Peak chloroquine concentrations in the controls varied between 69 ng ml-1 and 330 ng ml-1 (mean 134 +/- 99 ng ml-1). The mean AUC in the kwashiorkor children was significantly lower than the mean AUC in the control children (P less than 0.001). Peak plasma desethylchloroquine concentrations in the children with kwashiorkor varied between 3 and 13 ng ml-1 (mean 6 +/- 9 ng ml-1) while in the controls the concentrations varied between 14 and 170 ng ml-1 (mean 50 +/- 61 ng ml-1). There was no significant difference in the half-life of chloroquine between the kwashiorkor children and the normal control children. The possible influence of a different binding and distribution pattern of chloroquine in kwashiorkor could not be assessed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Whole-blood single-dose kinetics of chloroquine and desethylchloroquine in Africans.

The whole-blood kinetics of chloroquine and desethylchloroquine were studied in five healthy Ghanaian subjects. Chloroquine was rapidly absorbed, and peak concentrations were reached within 2 h. The drug disappeared from blood in a multiexponential manner, and the mean terminal half-life from day 7 to day 28 was 13 days. Desethylchloroquine concentrations were generally higher than those of chloroquine after 48 h. Renal clearance accounted for 65% of the apparent total clearance of chloroquine. The estimated mean total urinary recovery of the drug and its desethyl metabolite was 80% of the dose. Whole-blood concentrations of chloroquine offer some advantages compared with plasma concentrations, as this drug concentrates in the formed elements, and special precautions must be taken to obtain representative plasma concentrations.

Whole blood concentrations of chloroquine and desethylchloroquine during and after treatment of adult patients infected with Plasmodium vivax, P. ovale or P. malariae

Whole blood concentrations of chloroquine and desethychloroquine were determined during and after chloroquine treatment of 15 adult patients infected with P. vivax, P. ovale or P. malariae. The median of chloroquine concentrations remained practically unchanged in samples drawn three hours after initiation of treatment and in samples drawn immediately before the next dose of chloroquine. Concentrations of chloroquine remained above 1·0 μmol/litre for at least four days. The calculated sum of chloroquine and desethylchloroquine concentrations was above 1·0 μmol/litre for at least seven days. These concentrations are regarded as sufficient for treatment of P. vivax, P. ovale and P. malariae infections.

Determination of chloroquine and its desethyl metabolite in whole blood: an application for samples collected in capillary tubes and dried on filter paper.

A high performance liquid chromatography method for analysis of chloroquine and desethylchloroquine was adapted for 75 microliters aliquots of whole blood obtained by finger-prick and dried on filter paper. The precision of the method was satisfactory at whole blood concentrations of 40 nmol/L (coefficient of variation, 5%). The dried samples were stable for at least 7 weeks at 20 degrees C. The concentrations in venous whole blood and in dried samples correlated well. The correlation coefficient was 0.99 for chloroquine and 0.97 for desethylchloroquine. Chloroquine concentrations were marginally but significantly higher in venous whole blood. When fitted to a linear equation (y = bx + a) the relationship was y = 0.96x + 0.03. Desethylchloroquine concentrations did not differ significantly in venous whole blood and in finger-prick blood dried on filter paper. The method is specific and sensitive enough for pharmacokinetic studies and can be used in areas with limited technical facilities.

Plasma chloroquine and desethylchloroquine concentrations in children during and after chloroquine treatment for malaria.

Twelve children with acute falciparum malaria were treated with 25 mg/kg chloroquine orally in three divided doses at 24 h intervals. Concentrations of chloroquine and its metabolite, desethylchloroquine, were measured in plasma from the beginning of treatment for up to 7 days using a high pressure liquid chromatography (h.p.l.c.) technique. Chloroquine was detectable in plasma within 30 min of giving the drug. Peak level was reached in 1-8 h after the first dose of 10 mg/kg and the peak concentrations ranged between 65 and 263 ng/ml. Chloroquine concentration declined slowly in plasma after stopping drug administration so that the concentration at the seventh day was 37.5% of the concentration on the third day. The apparent half-life was 3-4 days. Desethylchloroquine was detectable in plasma within 30 min of giving chloroquine and peak levels were reached in 2-12 h. Peak concentration after the first dose of chloroquine ranged between 9 and 62 ng/ml. Desethylchloroquine was also slowly cleared from plasma and mean concentration at the end of 7 days was 49% of the mean concentration at the end of 3 days.

Sensitive method for the determination of chloroquine and its metabolite desethyl-chloroquine in human plasma and urine by high-performance liquid chromatography

A method has been developed for the rapid quantitative analysis of chloroquine and its metabolite desethyl-chloroquine in plasma, blood and urine using high-performance liquid chromatography. An ethylene dichloride extract of the alkalinized biological samples was extracted with dilute acid and chromatographed on a reversed-phase column. Phosphate buffer in acetonitrile was used as the mobile phase with perchlorate as the counter-ion. Ultraviolet absorption at 254 or 340 nm or fluorescence detection was used. The fluorescence spectra and the fluorescence quantum yield of the substances were determined. Chloroquine and desethyl-chloroquine concentrations in the range of 10 nmol/l (UV-detection) and of 0.5 nmol/l (fluorescence detection) could be accurately measured with a relative standard deviation of 12%. The method should be adequate for therapeutic and pharmacokinetic studies.