Absorption, Distribution and Excretion
The bioavailability of hydroxychloroquine is 67-74%. There is no significant difference in bioavailability between the R and S enantiomers. In healthy male volunteers, after a single oral dose of 200 mg hydroxychloroquine, the whole blood Cmax was 129.6 ng/mL (plasma Cmax was 50.3 ng/mL), and the Tmax was 3.3 hours (plasma Tmax was 3.7 hours). The mean fraction of absorption after a single oral dose of 200 mg hydroxychloroquine was 0.74 (compared to intravenous infusion of 155 mg hydroxychloroquine). The peak plasma concentrations of metabolites occur simultaneously with the peak plasma concentrations of hydroxychloroquine. After a single intravenous injection of 155 mg and 310 mg, the peak plasma concentrations at 6 months after the 155 mg infusion and 310 mg infusion ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL). Within the therapeutic dose range of 155 mg and 310 mg, pharmacokinetic parameters showed no significant difference, indicating linear pharmacokinetic characteristics. In patients with rheumatoid arthritis, drug absorption varied considerably (30% to 100%), with significantly higher mean hydroxychloroquine levels in patients with lower disease activity. 40-50% of hydroxychloroquine is excreted by the kidneys, with only 16-21% excreted unchanged in the urine. 5% is excreted through the skin, and 24-25% is excreted in the feces. Hydroxychloroquine is widely distributed in tissues; its volume of distribution in blood is 5522 liters, and in plasma it is 44257 liters. The clearance of hydroxychloroquine is 96 mL/min. The renal clearance of the unchanged drug is approximately 16% to 30%.

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Metabolism/Metabolites
Hydroxychloroquine undergoes N-dealkylation via CYP3A4 to produce the active metabolite desethylhydroxychloroquine and the inactive metabolites desethylchloroquine and bis-desethylchloroquine. Desethylhydroxychloroquine is the major metabolite.
Partially metabolized in the liver to the active desethylated metabolite.
Half-life: The terminal elimination half-life in the blood is approximately 50 days. In plasma, the half-life is approximately 32 days.

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Biological half-life
In healthy male volunteers, the plasma half-life after a single oral dose of 200 mg hydroxychloroquine is 123.5 days. Hydroxychloroquine is still detectable in urine 3 months later, with approximately 10% of the dose excreted unchanged. Results of a single 200 mg tablet versus an intravenous infusion (155 mg) showed a half-life of approximately 40 days and a larger volume of distribution. After long-term oral administration of hydroxychloroquine, the absorption half-life is approximately 3 to 4 hours, and the terminal half-life is 40 to 50 days.

Toxicity Summary
While the exact mechanism of action of hydroxychloroquine is not fully understood, it may be related to its ability to bind to and alter DNA. Studies have found that hydroxychloroquine can also be absorbed by the acidic food vesicles of the parasite within red blood cells. This increases the pH of the acidic vesicles, interfering with vesicle function and potentially inhibiting phospholipid metabolism. In suppressive therapy, hydroxychloroquine inhibits the developmental stage of Plasmodium within red blood cells. During acute malaria attacks, it blocks the parasite's schizogony within red blood cells. The ability of hydroxychloroquine to accumulate in infected red blood cells may explain its selective toxicity to the erythrocyte stage of Plasmodium infection. As an antirheumatic drug, hydroxychloroquine is considered to have mild immunosuppressive effects, inhibiting the production of rheumatoid factor and acute-phase reactants. It also accumulates in leukocytes, stabilizes lysosomal membranes, and inhibits the activity of many enzymes, including collagenase and proteases that lead to cartilage breakdown.

Pharmacodynamics
Hydroxychloroquine can affect the function of lysosomes in humans and Plasmodium. Altering lysosomal pH can reduce the presentation of low-affinity autoantigens in autoimmune diseases and interfere with Plasmodium's ability to hydrolyze hemoglobin to meet its energy needs. Hydroxychloroquine has a long duration of action, and in some indications it can be taken once weekly. Hydroxychloroquine may cause severe hypoglycemia; therefore, monitoring blood glucose levels is recommended for diabetic patients. Hydroxychloroquine is effective against the erythrocyte stages of chloroquine-sensitive Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale. Hydroxychloroquine is ineffective against the gametophyte and extraerythrocyte stages (including the dormant hepatic stage) of Plasmodium vivax and Plasmodium ovale. In areas where chloroquine resistance has been reported, hydroxychloroquine is ineffective against malaria.

C18H26N3OCL

335.87154

335.176

118-42-3

Hydroxychloroquine sulfate;747-36-4;Hydroxychloroquine-d4-1 sulfate;1216432-56-2;Hydroxychloroquine-d5

3652

White to off-white solid powder

1.176 g/cm3

516.7ºC at 760 mmHg

89-91°

266.3ºC

1.68E-11mmHg at 25°C

1.5790 (estimate)

3.856

2

4

9

23

331

0

CCN(CCCC(C)NC1=C2C=CC(=CC2=NC=C1)Cl)CCO

XXSMGPRMXLTPCZ-UHFFFAOYSA-N

InChI=1S/C18H26ClN3O/c1-3-22(11-12-23)10-4-5-14(2)21-17-8-9-20-18-13-15(19)6-7-16(17)18/h6-9,13-14,23H,3-5,10-12H2,1-2H3,(H,20,21)

2-[4-[(7-chloroquinolin-4-yl)amino]pentyl-ethylamino]ethanol

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 : ≥ 100 mg/mL (~297.73 mM)
1M HCl : 100 mg/mL (~297.73 mM)
H2O : ~1.67 mg/mL (~4.97 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.)