Treatment with amodiaquine (10–20 μM; 4 h) suppresses in a dose-dependent manner the expression of pro-inflammatory cytokines (IL-1β, interleukin-6, TNF-α, and iNOS) caused by lipopolysaccharide (PLS) [1]. TH+ neuron number and dopamine uptake analyses revealed that amodiaquine (5 μM; 24 h) effectively prevented neurotoxic (6-OHDA)-induced primary dopamine cell death. Additionally, amodiaquine was observed in rat PC12 cells. Modiquine's neuroprotective effects[1]

Amodiaquine (40 mg/kg; intraperitoneal; daily; for 3 days) treatment decreased perihematoma activation of astrocytes and microglia/macrophages in male ICR mice. In addition to improving motor impairment in mice, amodiaquine also reduces ICH-induced mRNA expression of IL-1β, CCL2, and CXCL2 [2].

RT-PCR[1]
Cell Types: primary microglia
Tested Concentrations: 10 µM, 15 µM, 20 µM
Incubation Duration: 4 hrs (hours)
Experimental Results: Inhibition of LPS-induced pro-inflammatory cytokines (IL-1β, interleukin-6, TNF-α, and iNOS) in a dose-dependent manner.

Animal/Disease Models: Male ICR mice (8-10 weeks old) induced intracerebral hemorrhage (ICH) [2]
Doses: 40 mg/kg
Route of Administration: intraperitoneal (ip) injection; daily; lasted for 3 days
Experimental Results: Microglia around the hematoma / diminished activation of macrophages and astrocytes.

Absorption, Distribution and Excretion
Absorption is rapid after oral administration. Amodiaquine hydrochloride is readily absorbed from the gastrointestinal tract. It is rapidly converted in the liver to the active metabolite desethylamomodiaquine, which contributes almost all of the antimalarial effect (10). Data on the terminal plasma elimination half-life of desethylamomodiaquine are insufficient. Amodiaquine and desethylamomodiaquine were detectable in urine several months after administration. Absorption is rapid after oral administration of amodiaquine hydrochloride… In 7 healthy adult men, after oral administration of amodiaquine (600 mg)… the peak concentration of amodiaquine was 32 ± 3 ng/mL at 0.5 ± 0.03 hours. The peak concentrations of amodiaquine in whole blood and packed erythrocytes were 60 ± 10 ng/mL and 42 ± 6 ng/mL, respectively, both reached at 0.5 ± 0.1 hours. Thereafter, the concentration of amodiaquine rapidly decreased and became undetectable within 8 hours. The mean peak plasma concentration of the metabolite (desethylamomodine) was 181 ± 26 ng/mL. The time to peak concentration in whole blood and packed red blood cells was 2.2 ± 0.5 h and 3.6 ± 1.1 h, respectively. For more complete data on absorption, distribution, and excretion of amodiaquine (10 items in total), please visit the HSDB record page. The main elimination route of amodiaquine is via hepatic biotransformation to desethylamomodine (the major bioactive metabolite). Due to a significant first-pass effect, almost no unconverted drug of orally administered amodiaquine enters the systemic circulation. …Amodiaquine hydrochloride…is rapidly and extensively metabolized to desethylamomodine, which is concentrated in blood cells. Desethylamomodine, rather than amodiaquine, is likely the source of most of the observed antimalarial activity, and the toxicity of orally administered amodiaquine may be partly attributed to desethylamomodine.
After oral administration of amodiaquine, the levels of the parent compound in the blood are relatively low. The main clearance pathway of amodiaquine is through hepatic biotransformation to desethylamodiaquine (the main bioactive metabolite). Due to the significant first-pass effect, almost no unconverted metabolites of orally administered amodiaquine enter the systemic circulation.
To further understand the presumed metabolic reasons for the hepatotoxicity limiting the use of amodiaquine, we investigated the hepatic metabolism of amodiaquine. In anesthetized rats, after portal vein injection (54 μmol/kg), the drug was primarily excreted in the bile as a thioether conjugate (23 ± 3% of the dose excreted within 5 hours; mean ± standard deviation, n = 6). Within 24 hours after portal vein injection, 20% of the dose was excreted in the urine as the parent compound, as well as N-dealkylation and oxidative deamination products. Desethylamodiaquine accumulates in the liver, but by examining the excretion of glutathione adducts in bile, it was found not to be a bioactive substrate. Pre-administration of the P450 inhibitor ketoconazole reduced bile excretion by 50% and correspondingly decreased the amount of drug irreversibly bound to liver proteins. This suggests that P450 plays a role in the bioactivation of amodiaquine to its active metabolite, which binds to glutathione and proteins. Deethylation and irreversible binding were observed in vitro using male rat liver microsomes, and ketoconazole again inhibited these reactions. However, despite significant conversion of amodiaquine to desethylamodiaquine, such binding was not observed in human (6 subjects) liver microsomes. The amodiaquinone imine was rapidly reduced in the presence of human or rat liver microsomes. Therefore, in vitro studies may underestimate the in vivo bioactivation of amodiaquine. These data suggest that the extent of protein adduct formation in the liver depends on the relative rates of amodiaquine oxidation and its quinone imine reduction. This, in turn, may be a contributing factor to amodiaquine-specific hepatotoxicity. Replacing the phenolic hydroxyl group in amodiaquine with fluoride blocks the bioactivation of the drug in vivo. The introduction of the N-hydroxyethyl functional group enables partial clearance of amodiaquine and its dehydroxyfluoro analogues via O-glucuronidation and alters the balance between phase I oxidation and direct phase II binding of amodiaquine. The metabolism of amodiaquine (AQ) to N-deethylamodiaquine (DEAQ) is its primary metabolic pathway in humans. The authors used human liver microsomes and two groups of recombinant human cytochrome P450 isoenzymes (derived from lymphoblasts and yeast, respectively) to identify CYP isoenzymes involved in AQ metabolism. CYP2C8 is the main hepatic isoenzyme that clears AQ and catalyzes the formation of DEAQ. Extrahepatic P450 enzymes 1A1 and 1B1 also clear AQ and catalyze the formation of an unknown metabolite, M2. The Km and Vmax values for recombinant CYP2C8 in the N-deethylation of AQ were 1.2 μM and 2.6 pmol/min/pmol CYP2C8, respectively, while the corresponding values for human liver microsomes (HLM) were 2.4 μM and 1462 pmol/min/mg protein, respectively. The relative contribution of CYP2C8 to DEAQ generation was estimated to be 100% using the relative activity factor method. Correlation analysis of AQ metabolism and the activities of eight hepatic P450 enzymes was performed on 10 different HLM samples. Both DEAQ generation and AQ clearance showed excellent correlations with 6α-hydroxylation of paclitaxel, a hallmark substrate of CYP2C8 (r² 0.98 and 0.95, respectively). Quercetin exhibited competitive inhibition of DEAQ generation, with Ki values of 1.96 μM for CYP2C8 and 1.56 μM for HLM. Homology modeling of AQ docking to the active site of the CYP2C isoenzyme revealed a favorable interaction between AQ and CYP2C8, supporting the possibility of N-deethylation. These data indicate that CYP2C8 is the major hepatic isoenzyme responsible for AQ metabolism. The specificity, high affinity, and high turnover rate of AQ deethylation make it an excellent marker of CYP2C8 activity.

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Biological Half-Life
5.2 ± 1.7 minutes (range 0.4 to 5.5) after oral administration of 600 mg amodiaquine, and the geometric mean of the estimated elimination phase half-life was 2.1 hours (range 0.5 to 5.7).

Hepatotoxicity
Amodiaquine has been associated with elevated serum transaminases in a small percentage of patients (1%). More importantly, there have been several reports of specific acute liver injury caused by amodiaquine. The injury typically develops within 1 to 4 months and is often accompanied by agranulocytosis. The most common pattern of elevated serum enzymes is hepatocellular, with typical symptoms resembling acute viral hepatitis. Hypersensitivity reactions and autoantibodies are uncommon. Hepatitis can be severe, with several reported cases of death or requiring urgent liver transplantation. The incidence of severe liver injury is estimated to be approximately 1 in 15,000. Due to the risk of agranulocytosis and liver injury, amodiaquine is no longer recommended for malaria prophylaxis and is primarily used for treatment in malaria-endemic areas outside the United States. General recommendations for malaria treatment, including specific details regarding diagnosis, treatment, drug dosage, and safety, are available at the Centers for Disease Control and Prevention (CDC) website: http://www.cdc.gov/malaria/. Probability Score: A (Etiology of clinically established liver injury).

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Drug Interactions
Since concomitant use of magnesium trisilicate and kaolin is known to reduce the gastrointestinal absorption of chloroquine, it is likely that it will also reduce the absorption of amodiaquine.
Concomitant use of a recommended dose of chloroquine (used to suppress malaria chemoprevention) during intradermal rabies vaccination for pre-exposure prophylaxis may interfere with the antibody response to the vaccine. However, the clinical significance of this interaction is yet to be determined, but it should be considered and may be related to the situation with amodiaquine.
Concomitant use with other antimalarial drugs should be avoided, and regular laboratory tests should be performed to ensure that blood markers and liver function test results remain within normal ranges.

[1]. Chun-Hyung Kim, et al. Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease. Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8756-61.
[2]. Keita Kinoshita, et al. A Nurr1 agonist amodiaquine attenuates inflammatory events and neurological deficits in a mouse model of intracerebral hemorrhage. J Neuroimmunol. 2019 May 15;330:48-54.
[3]. Akira Yokoyama, et al. Effect of amodiaquine, a histamine N-methyltransferase inhibitor, on, Propionibacterium acnes and lipopolysaccharide-induced hepatitis in mice. Eur J Pharmacol. 2007 Mar 8;558(1-3):179-84.
[4]. M T HOEKENGA. The treatment of acute malaria with single oral doses of amodiaquin, chloroquine, hydroxychloroquine and pyrimethamine. Am J Trop Med Hyg. 1954 Sep;3(5):833-8.

Therapeutic Uses
Treatment Category: Antimalarial Drugs Recent data on the in vivo sensitivity of Plasmodium ovale and Plasmodium to malaria drugs are very limited. Although there has been a recent report of resistance to chloroquine in Plasmodium, both species are considered highly sensitive to chloroquine. Experience suggests that Plasmodium ovale and Plasmodium are also sensitive to amodiaquine, mefloquine, and artemisinin derivatives. Summary of recommendations for treating uncomplicated vivax malaria: For chloroquine-resistant vivax malaria, amodiaquine (30 mg/kg body weight, divided into 3 doses, once daily, 10 mg/kg body weight) in combination with primaquine should be used. Indications/For/Treatment/Acute malaria attacks in non-immune populations. It is at least as effective as chloroquine and is also effective against some chloroquine-resistant strains, although there have been reports of amodiaquine resistance.

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Drug Warning
Recent reports have documented seven cases of agranulocytosis associated with the use of amodiquine for malaria prophylaxis in British travelers (1). An additional 16 cases of agranulocytosis associated with amodiquine use have recently been reported to the drug manufacturer in Western Europe, and the US Centers for Disease Control and Prevention (CDC) has received reports of two US cases. Of these 25 cases, 23 occurred in 1985 or 1986, and seven of them were reported to have died. In 20 cases where the duration of amodiquine prophylaxis was known, the duration ranged from 3 to 24 weeks. In all but four of the 25 cases, amodiquine was administered at an appropriate dose (400 mg bases per week for adults) for prophylaxis. It is known that 14 of these patients were also using other antimalarial drugs for prophylaxis… It now appears that any prophylactic advantage that amodiquine may offer does not outweigh the risk of agranulocytosis it may cause. Therefore, the U.S. Centers for Disease Control and Prevention (CDC) no longer recommends the use of amodiaquine for prophylaxis. Because amodiaquine can accumulate in the liver, it should be used with caution in patients with liver disease, alcoholism, or those taking hepatotoxic drugs. Children are particularly sensitive to 4-aminoquinoline derivatives. Due to the narrow range between therapeutic and toxic concentrations in children, parenteral administration of amodiaquine should not be performed in this age group. Amodiaquine is contraindicated in patients with hypersensitivity to 4-aminoquinoline derivatives. For more complete data on amodiaquine (14 in total), please visit the HSDB records page.

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Pharmacodynamics
Amodiaquine is a 4-aminoquinoline drug with a structure and activity similar to chloroquine and has been used as an antimalarial and anti-inflammatory drug for over 40 years. Amodiaquine is at least as effective as chloroquine and is effective against some chloroquine-resistant strains, but resistance to amodiaquine has been reported. The mechanism of action of amodiaquine has not been determined. 4-Aminoquinoline drugs can inhibit the myocardium, impair cardiac conduction, and cause vasodilation, leading to hypotension. They can also suppress respiration and cause double vision, dizziness, and nausea.

355.145

86-42-0

Amodiaquine dihydrochloride dihydrate;6398-98-7;Amodiaquine-d10;1189449-70-4;Amodiaquine dihydrochloride;69-44-3

2165

Crystals from absolute ethanol

1.3±0.1 g/cm3

478.0±45.0 °C at 760 mmHg

208°C

242.9±28.7 °C

0.0±1.2 mmHg at 25°C

1.669

4.77

2

4

6

25

406

0

OVCDSSHSILBFBN-UHFFFAOYSA-N

InChI=1S/C20H22ClN3O/c1-3-24(4-2)13-14-11-16(6-8-20(14)25)23-18-9-10-22-19-12-15(21)5-7-17(18)19/h5-12,25H,3-4,13H2,1-2H3,(H,22,23)

4-[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol

Camochin Camoquin Camoquinal Camoquine Flavoquine Miaquin NSC 13453 SN-10751

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~66.67 mg/mL (~187.35 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)