Drug Interaction of Chloroquine with Ciclosporin

Nampoory, M.R.N.; Nessim, J; Gupta, Rajesh; Johny, K.V.

doi:10.1159/000187007

Cited by 30 publications

(20 citation statements)

References 2 publications

(2 reference statements)

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“…17 If chloroquine therapy is considered, up to 3-fold increases in cyclosporine levels can be expected. 18,19 The mechanism remains unknown albeit confirmed after rechallenge. The FDA chloroquine label warns for increased cyclosporine levels when coadministered, whereas no such effect is seen with tacrolimus.…”

Section: Discussionmentioning

confidence: 99%

Severe COVID-19 in a renal transplant recipient: A focus on pharmacokinetics

Meziyerh

Zwart

Etten

et al. 2020

American Journal of Transplantation

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Section: Discussionmentioning

confidence: 99%

Severe COVID-19 in a renal transplant recipient: A focus on pharmacokinetics

Meziyerh

Zwart

Etten

et al. 2020

American Journal of Transplantation

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“…In vivo, coadministration of CQ and dapsone to volunteers did not affect CYP3A4-mediated dapsone metabolism (Adedoyin et al, 1998). In contrast, coadministration of CQ with cyclosporine, a CYP3A4 and P-glycoprotein (P-gp) substrate, led to an increase in cyclosporine plasma levels and transient nephrotoxicity (Nampoory et al, 1992). Since P-gp is an important determinant of interpatient variability in oral cyclosporine bioavailability (Tsuji and Tamai, 1996) and because CQ has been shown to interfere with P-gp function in vitro (Tiberghien and Loor, 1996), one could speculate that an interaction with P-gp rather than CYP3A4 could be responsible for the CQ-cyclosporine interaction.…”

Section: Chloroquine N-desethylation By Cyp2c8 Cyp3a4 and Cyp2d6mentioning

confidence: 99%

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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“…Although pharmacokinetic interactions can hence be expected in combination with CYP-inhibiting drugs [9], chloroquine is more infamous for its role as a perpetrator drug in several interactions. For example, higher concentrations of cyclosporine [27,28] and potentially of P-glycoprotein substrates such as digoxin [9], dabigatran, or edoxaban have been described, even though digoxin and chloroquine were combined successfully in a case of…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 99%

Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties

et al. 2020

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Since in vitro studies and a preliminary clinical report suggested the efficacy of chloroquine for COVID-19-associated pneumonia, there is increasing interest in this old antimalarial drug. In this article, we discuss the pharmacokinetics and safety of chloroquine that should be considered in light of use in SARS-CoV-2 infections. Chloroquine is well absorbed and distributes extensively resulting in a large volume of distribution with an apparent and terminal half-life of 1.6 days and 2 weeks, respectively. Chloroquine is metabolized by cytochrome P450 and renal clearance is responsible for one third of total clearance. The lack of reliable information on target concentrations or doses for COVID-19 implies that for both adults and children, doses that proved effective and safe in malaria should be considered, such as 'loading doses' in adults (30 mg/kg over 48 h) and children (70 mg/kg over 5 days), which reported good tolerability. Here, plasma concentrations were < 2.5 μmol/L, which is associated with (minor) toxicity. While the influence of renal dysfunction, critical illness, or obesity seems small, in critically ill patients, reduced absorption may be anticipated. Clinical experience has shown that chloroquine has a narrow safety margin, as three times the adult therapeutic dosage for malaria can be lethal when given as a single dose. Although infrequent, poisoning in children is extremely dangerous where one to two tablets can potentially be fatal. In conclusion, the pharmacokinetic and safety properties of chloroquine suggest that chloroquine can be used safely for an acute virus infection, under corrected QT monitoring, but also that the safety margin is small, particularly in children.

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Drug Interaction of Chloroquine with Ciclosporin

Cited by 30 publications

References 2 publications

Severe COVID-19 in a renal transplant recipient: A focus on pharmacokinetics

Severe COVID-19 in a renal transplant recipient: A focus on pharmacokinetics

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

Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties

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