Disease relevance of Monodesethylchloroquine

• The pharmacokinetics of chloroquine and its main metabolite desethylchloroquine have been carried out in volunteers with and without chloroquine-induced pruritus [1].
• 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) [2].
• The pharmacokinetics of chloroquine (CQ) and desethylchloroquine (DECQ) were studied in seven male Thai patients with P. vivax malaria and seven healthy male Thais, after the standard oral dosage regimen of CQ (a total dose of 1500 mg given over 3 days) [3].

High impact information on Monodesethylchloroquine

• Following administration chloroquine is rapidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmacologically active desethylchloroquine and bisdesethylchloroquine [4].
• In vitro and in vivo, chloroquine and desethylchloroquine competitively inhibit CYP2D1/6-mediated reactions [4].
• Chloroquine, its principal metabolite monodesethylchloroquine and doxycycline were also measured by high performance liquid chromatography (HPLC) [5].
• Protein binding of chloroquine enantiomers and desethylchloroquine [6].
• Simultaneous determination of monodesethylchloroquine, chloroquine, cycloguanil and proguanil on dried blood spots by reverse-phase liquid chromatography [7].

Chemical compound and disease context of Monodesethylchloroquine

• In the absence of promethazine there appears to be an extensive metabolism of chloroquine in hypersensitive individuals to produce monodesethylchloroquine which probably determines the degree of pruritus experienced by an individual [8].

Biological context of Monodesethylchloroquine

• RESULTS: The blood concentration Area Under the Curve (AUC) of group B was about 10% larger than that of group A. The total amounts of CQ plus deethylchloroquine excreted with the urine during the 72-h study period were 5% for group A and 6% for group B. None of the pharmacokinetic parameters were significantly different between the two groups [9].
• The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects [10].
• Treatment outcomes were assessed by microscopical diagnoses, PCR-based confirmation of the diagnoses, measurement of the whole-blood concentrations of CQ and desethylchloroquine (DCQ), and identification of the Plasmodium falciparum genotypes [11].
• Patients who had PCT < or = 24 h and those with PCT >24 h had comparable IC50 to chloroquine (alone and plus primaquine) and quinine, as well as similar concentrations of chloroquine/desethylchloroquine (in blood) or quinine (in plasma) at the investigated time points [12].

Anatomical context of Monodesethylchloroquine

• 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 [13].
• The desethylchloroquine metabolite blood concentrations were low relative to the drug, although the metabolite was detected in all blood samples including the initial 5 min maternal blood samples and 15 min fetal blood samples [14].
• Blood concentrations of chloroquine and desethylchloroquine in the mother and fetuses were assayed using HPLC [14].

Associations of Monodesethylchloroquine with other chemical compounds

• Chloroquine, desethylchloroquine, and methylene blue concentrations were determined by means of HPLC/UV or LC/MS/MS assays in whole blood, plasma, and urine for 28 days after the last dose [15].
• Plasmodium falciparum: modulation by calcium antagonists of resistance to chloroquine, desethylchloroquine, quinine, and quinidine in vitro [16].
• Chloroquine, monodesethylchloroquine, diazepam, and nordiazepam levels are simultaneously determined in whole blood or plasma by HPLC [17].
• A study using chemical inhibitors showed only quercetin (a CYP2C8 inhibitor) and ketoconazole (a CYP3A4/5 inhibitor) inhibited the DCQ formation [18].

Gene context of Monodesethylchloroquine

• In addition, the DCQ formation significantly correlated with the CYP3A4/5-catalyzed midazolam 1-hydroxylation (r = 0.868) and CYP2C8-catalyzed paclitaxel 6alpha-hydroxylation (r = 0.900) [18].
• Of the cDNA-expressing CYPs examined, CYP1A2, 2C8, 2C19, 2D6 and 3A4/5 exhibited significant DCQ formation [18].

Analytical, diagnostic and therapeutic context of Monodesethylchloroquine

• 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 [19].
• The samples were assayed for chloroquine and monodesethylchloroquine using a combination of thin-layer chromatography and spectrophotometry [20].
• Since the biological activities of desethylchloroquine and chloroquine are not the same, drug monitoring should be performed with a method distinguishing between the parent drug and the metabolite [21].
• The major metabolite of chloroquine, (+)-desethylchloroquine, produced by stereoselective N-dealkylation of the drug, was obtained in 81.5% enantiomeric purity by resolution of racemic desethylchloroquine using an atropisomeric resolving agent and was shown by circular dichroism to have the absolute (S)-configuration [22].
• There was a 47.04% reduction in the AUC0-7d of monodesethylchloroquine, the major metabolite of chloroquine, in the test group when compared with the control group [20].

References