Protein binding of chloroquine enantiomers and desethylchloroquine.

Ofori‐Adjei, David; Ericsson, Örjan; Lindström, Björn; Sjöqvist, Folke

doi:10.1111/j.1365-2125.1986.tb02900.x

Cited by 54 publications

(18 citation statements)

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“… 16 , 65 Extend of S(+)-chloroquine plasma protein binding is greater than binding of R(-)-chloroquine (67% vs 35%). 66 Binding of hydroxychloroquine to plasma proteins is around 50%, which is less than chloroquine binding. The S-hydroxychloroquine is 64% bound to plasma proteins, while the R-hydroxychloroquine is only 37% protein bound.…”

Section: Resultsmentioning

confidence: 99%

<p>Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine</p>

Babayeva¹,

Loewy²

2020

PGPM

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Background A new coronavirus SARS-CoV-2 has been identified as the etiological agent of the severe acute respiratory syndrome, COVID-19, the source and cause of the 2019–20 coronavirus pandemic. Hydroxychloroquine and chloroquine have gathered extraordinary attention as therapeutic candidates against SARS-CoV-2 infections. While there is growing scientific data on the therapeutic effect, there is also concern for toxicity of the medications. The therapy of COVID-19 by hydroxychloroquine and chloroquine is off-label. Studies to analyze the personalized effect and safety are lacking. Methods A review of the literature was performed using Medline/PubMed/Embase database. A variety of keywords were employed in keyword/title/abstract searches. The electronic search was followed by extensive hand searching using reference lists from the identified articles. Results A total of 126 results were obtained after screening all sources. Mechanisms underlying variability in drug concentrations and therapeutic response with chloroquine and hydroxychloroquine in mediating beneficial and adverse effects of chloroquine and hydroxychloroquine were reviewed and analyzed. Pharmacogenomic studies from various disease states were evaluated to elucidate the role of genetic variation in drug response and toxicity. Conclusion Knowledge of the pharmacokinetics and pharmacogenomics of chloroquine and hydroxychloroquine is necessary for effective and safe dosing and to avoid treatment failure and severe complications.

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Section: Resultsmentioning

confidence: 99%

<p>Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine</p>

Babayeva¹,

Loewy²

2020

PGPM

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“…7,8 Chloroquine binding to plasma proteins is concentration independent; there is a modest steroselective difference because 66.6% of the (+)-chloroquine and 45.9% of (−)-chloroquine is bound to plasma proteins. 9 Approxi- mately 50% of a given dose is recovered unchanged in the urine. Chloroquine is metabolized predominately through dealklyation to desethylchloroquine, bis desethylchloroquine, and 7-chlor-4-aminoquinoline.…”

Section: Discussionmentioning

confidence: 99%

Lack of a Pharmacokinetic Interaction Between Azithromycin and Chloroquine

Cook

Randinitis

Bramson

et al. 2006

The American Journal of Tropical Medicine and Hygiene

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A study was conducted to investigate a possible pharmacokinetic interaction between azithromycin and chloroquine. Twenty-four subjects received azithromycin, 1,000 mg a day for three days, followed by a washout period, then azithromycin, 1,000 mg plus chloroquine 600 mg base on days 1 and 2, and azithromycin, 1,000 mg plus chloroquine 300 mg base on day 3 of the final period. A second group of 16 subjects received chloroquine, 600 mg base on days 1 and 2, then 300 mg base on day 3. Blood samples were obtained serially up to 624 hours after the day 3 dose in each period. Log transformed maximum concentration and area under the curve values of azithromycin and chloroquine were compared using 90% confidence intervals calculated from appropriate analysis of variance models. Ninety percent confidence intervals for all pharmacokinetic parameters were contained within the interval 80-125%, which indicates the absence of a clinically relevant pharmacokinetic interaction.

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“…CQ is 50% to 60% bound to plasma proteins (Ofori-Adjei et al 1986) and has a very long terminal elimination half-life (t1 / 2 ) of 1 to 2 months, with a relatively high total body clearance (CL) of about 1 L/h/kg as calculated from the plasma data (Frisk-Holmberg et al 1984). Redistribution processes from the tissues to intravascular compartments are believed to be the factors primarily responsible for maintaining CQ blood concentrations for such long periods of time (Frisk-Holmberg, Bergqvist, and Termond 1985).…”

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confidence: 99%

Pharmacokinetics of the Antimalarial Drug, AQ-13, in Rats and Cynomolgus Macaques

et al. 2004

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The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats (n = 4/sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved C(max) after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and C(max) values following single oral dose administration were not dose proportional; the C(max) value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. Monodesethyl AQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding C(max) values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism of AQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.

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Protein binding of chloroquine enantiomers and desethylchloroquine.

Cited by 54 publications

References 5 publications

<p>Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine</p>

<p>Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine</p>

Lack of a Pharmacokinetic Interaction Between Azithromycin and Chloroquine

Pharmacokinetics of the Antimalarial Drug, AQ-13, in Rats and Cynomolgus Macaques

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