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
Rapidly absorbed following oral administration.
Amodiaquine hydrochloride is readily absorbed from the gastrointestinal tract. It is rapidly converted in the liver to the active metabolite desethylamodiaquine, which contributes nearly all of the antimalarial effect (10). There are insufficient data on the terminal plasma elimination half-life of desethylamodiaquine. Both amodiaquine and desethylamodiaquine have been detected in the urine several months after administration.
After oral administration amodiaquine hydrochloride is rapidly absorbed...
After oral administration of amodiaquine (600 mg) to 7 healthy adult males ... The peak concentration of amodiaquine was 32 +/- 3 ng/mL at 0.5 +/- 0.03 hr. The peak concentrations of amodiaquine in whole blood and packed cells were 60 +/- 10 and 42 +/- 6 ng/mL respectively, reached at 0.5+/- 0.1hr in both. Thereafter the concentration of amodiaquine declined rapidly, and was detectable for no more than 8 hr.
Mean peak plasma concentration of the metabolite (desethylamodiaquine) was 181 +/- 26 ng/mL. Times to peak for whole blood and packed cells were 2.2 +/- 0.5 and 3.6 +/- 1.1 hr respectively
For more Absorption, Distribution and Excretion (Complete) data for AMODIAQUINE (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation.
... Amodiaquine hydrochloride ... undergoes rapid and extensive metabolism to desethylamodiaquine which concentrates in blood cells. It is likely that desethylamodiaquine, not amodiaquine, is responsible for most of the observed antimalarial activity, and that the toxic effects of amodiaquine after oral administration may in part be due to desethylamodiaquine.
When amodiaquine is given orally relatively little of the parent compound is present in the blood. Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation.
The hepatic metabolism of the antimalarial drug amodiaquine was investigated in order to gain further insight into the postulated metabolic causation of the hepatotoxicity, which restricts the use of the drug. After intraportal administration (54 mumol/kg) to the anaesthetized rat, the drug was excreted in bile (23 +/- 3% dose over 5 h; mean +/- SD, n = 6) primarily as thioether conjugates. After intraportal administration, 20% of the dose was excreted into urine over 24 h as parent compound and products of N-dealkylation and oxidative deamination. Desethylamodiaquine accumulated in liver, but was not a substrate for bioactivation as measured by biliary elimination of a glutathione adduct. Prior administration of ketoconazole, an inhibitor of P450, reduced biliary excretion by 50% and effected a corresponding decrease in the amount of drug irreversibly bound to liver proteins. This indicated a role for P450 in the bioactivation of amodiaquine to a reactive metabolite that conjugates with glutathione and protein. De-ethylation and irreversible binding were observed in vitro using male rat liver microsomes, and were again inhibited by ketoconazole. However, no such binding was observed with human (six individuals) hepatic microsomes despite extensive turnover of amodiaquine to desethylamodiaquine. Amodiaquine quinoneimine underwent rapid reduction in the presence of either human or rat liver microsomes. Therefore in vitro studies may underestimate the bioactivation of amodiaquine in vivo. These data indicate that the extent of protein adduct formation in the liver will depend on the relative rates of oxidation of amodiaquine and reduction of its quinoneimine. This in turn may be a predisposing factor in the idiosyncratic hepatotoxicity associated with amodiaquine. Substitution of a fluorine for the phenolic hydroxyl group in amodiaquine blocked bioactivation of the drug in vivo. Insertion of an N-hydroxyethyl function enabled partial clearance of amodiaquine and its deshydroxyfluoro analogue via O-glucuronidation and altered the balance between phase I oxidation and direct phase II conjugation of amodiaquine.
Amodiaquine (AQ) metabolism to N-desethylamodiaquine (DEAQ) is the principal route of disposition in humans. Using human liver microsomes and two sets of recombinant human cytochrome P450 isoforms (from lymphoblastoids and yeast) /the authors/ performed studies to identify the CYP isoform(s) involved in the metabolism of AQ. CYP2C8 was the main hepatic isoform that cleared AQ and catalyzed the formation of DEAQ. The extrahepatic P450s, 1A1 and 1B1, also cleared AQ and catalyzed the formation of an unknown metabolite M2. The K(m) and V(max) values for AQ N-desethylation were 1.2 microM and 2.6 pmol/min/pmol of CYP2C8 for recombinant CYP2C8, and 2.4 microM and 1462 pmol/min/mg of protein for human liver microsomes (HLMs), respectively. Relative contribution of CYP2C8 in the formation of DEAQ was estimated at 100% using the relative activity factor method. Correlation analyses between AQ metabolism and the activities of eight hepatic P450s were made on 10 different HLM samples. Both the formation of DEAQ and the clearance of AQ showed excellent correlations (r(2) = 0.98 and 0.95) with 6alpha-hydroxylation of paclitaxel, a marker substrate for CYP2C8. The inhibition of DEAQ formation by quercetin was competitive with K(i) values of 1.96 for CYP2C8 and 1.56 microM for HLMs. Docking of AQ into the active site homology models of the CYP2C isoforms showed favorable interactions with CYP2C8, which supported the likelihood of an N-desethylation reaction. These data show that CYP2C8 is the main hepatic isoform responsible for the metabolism of AQ. The specificity, high affinity, and high turnover make AQ desethylation an excellent marker reaction for CYP2C8 activity.

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Biological Half-Life
5.2 ± 1.7 (range 0.4 to 5.5) minutes
Amodiaquine 600 mg was given by mouth, the apparent terminal half-life of amodiaquine was 5.2 + 1.7 (range 0.4 to 5.5) minutes and the geometric mean of the estimated elimination phase half-lives was 2.1 (range 0.5 to 5.7) hours.

Hepatotoxicity
Amodiaquine has been linked to serum aminotransferase elevations in a small proportion of patients (1%). More importantly, there have been multiple reports of idiosyncratic acute liver injury due to amodiaquine. The onset of injury is usually within 1 to 4 months and is often associated with agranulocytosis. The pattern of serum enzyme elevations is most frequently hepatocellular, and symptoms resembling acute viral hepatitis are typical. Features of hypersensitivity are uncommon, as are autoantibodies. The hepatitis can be severe, and several fatal instances or cases requiring emergency liver transplantation have been reported. The frequency of serious hepatic injury is estimated to be ~1:15,000. Because of the risks of agranulocytosis and liver injury, amodiaquine is no longer recommended for use as prophylaxis against malaria and is used largely for therapy in endemic areas outside of the United States. General recommendations on the therapy of malaria including specific details on diagnosis, management, drug dosage and safety are available at the CDC website: http://www.cdc.gov/malaria/.
Likelihood score: A (well established cause of clinically apparent liver injury).

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Interactions
Since magnesium trisilicate and kaolin are known to decrease the gastrointestinal absorption of chloroquine when administered simultaneously, it is likely that this also follows for amodiaquine.
Concomitant administration of chloroquine at recommended doses for malaria suppression of chemoprophylaxis during pre-exposure prophylaxis of rabies with intra-dermally administered rabies vaccine may interfere with the antibody response to the vaccine. However, the clinical significance of this interaction remains to be clearly established but should be considered and may have relevance in the case of amodiaquine.
Concomitant use with other antimalarials should be avoided and regular laboratory investigations should be performed to assure that blood values and liver function tests remain within normal limits.

[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
THERAP CAT: Antimalarial
There are very few recent data on the in vivo susceptibility of P. ovale and P. malariae to antimalarials. Both species are regarded as very sensitive to chloroquine, although there is a single recent report of chloroquine resistance in P. malariae. Experience indicates that P. ovale and P. malariae are also susceptible to amodiaquine, mefloquine and the artemisinin derivatives.
Summary of recommendations on the treatment of uncomplicated vivax malaria: Amodiaquine (30 mg base/kg bw divided over 3 days as 10 mg/kg bw single daily doses) combined with primaquine should be given for chloroquine-resistant vivax malaria.
/Indicated/ for /the/ treatment of acute malarial attacks in non-immune subjects. It is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported.

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Drug Warnings
Agranulocytosis Associated with the Use of Amodiaquine for Malaria Prophylaxis Seven cases of agranulocytosis associated with the use of amodiaquine (Camoquine) among British travelers have recently been reported (1). Sixteen additional cases of agranulocytosis from Western Europe associated with the use of amodiaquine have recently been reported to the drug manufacturer, and two U.S. cases have been reported to CDC. Twenty-three of these 25 cases occurred in 1985 or 1986, and seven are reported to have been fatal. Among 20 cases for which the duration of amodiaquine prophylaxis is known, usage ranged from 3 weeks to 24 weeks. In all but four of the 25 cases, amodiaquine was used at the appropriate dosage (adults 400 mg base per week) for prophylaxis. Fourteen of the patients are known to have used another antimalarial drug concurrently for prophylaxis ... It is now apparent that any possible prophylactic advantage that amodiaquine may afford is not justified by the possible risk of agranulocytosis associated with the use of the drug. CDC, therefore, no longer recommends that amodiaquine be used for prophylaxis.
Because amodiaquine may concentrate in the liver, the drug should be used with caution in patients with hepatic disease or alcoholism, and in patients receiving hepatotoxic drugs.
Children are especially sensitive to 4-aminoquinoline derivatives. Because of the narrow margin between the therapeutic and toxic concentrations in children, amodiaquine should not be administered parenterally in this age group.
Amodiaquine is contraindicated in patients who are hypersensitive /to 4-aminoquinoline derivatives/.
For more Drug Warnings (Complete) data for AMODIAQUINE (14 total), please visit the HSDB record page.

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Pharmacodynamics
Amodiaquine, a 4-aminoquinoline similar to chloroquine in structure and activity, has been used as both an antimalarial and an anti-inflammatory agent for more than 40 years. Amodiaquine is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported. The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension. They depress respiration and cause diplopia, 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.)