How toxic are chloroquine and hydroxychloroquine to cells?

The spread of the pandemic disease COVID-19 caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has now reached almost every country of the world, with over 3.11 million cases and over 217,000 deaths as of April 29, 2020.

Clinical features of severe COVID-19

Most patients have mild or asymptomatic disease, but 20% or so of patients have more severe disease. Overall, critical or very severe disease occurs in about 5% of patients.

These patients have cardiac arrhythmias, acute kidney disease, pulmonary edema, septic shock, and acute respiratory distress syndrome (ARDS). Other vital organs are also affected in some patients, such as the heart, kidneys, liver, or digestive tract, causing multi-organ damage. Individuals who are older or have underlying medical conditions are at high risk for severe disease and death.

The promise of chloroquine and hydroxychloroquine

In the absence of a vaccine or new therapeutic agent, older approved drugs are being explored to test if they can be repurposed against COVID-19. Experiments show that the SARS-CoV-2 virus was inhibited by the antimalarial chloroquine and its derivative, hydroxychloroquine in vitro. Both drugs have been commercially produced for the treatment of malaria for decades. Hydroxychloroquine is also used in the treatment of several autoimmune disorders like systemic lupus erythematosus (SLE).

Study: Cytotoxicity evaluation of chloroquine and hydroxychloroquine in multiple cell lines and tissues by dynamic imaging system and PBPK model. Image Credit: Nikolay Litov / Shutterstock
Study: Cytotoxicity evaluation of chloroquine and hydroxychloroquine in multiple cell lines and tissues by dynamic imaging system and PBPK model. Image Credit: Nikolay Litov / Shutterstock

Clinical trials showed both drugs performed better than the control group in controlling pneumonia and preventing it from worsening, improving the findings on lung imaging, accelerating seroconversion, and shortening the course of the disease.

The drugs may act by blocking the entry of the virus into the host cell, could inhibit glycosylation, and increase the pH of endosomes and lysosomes. Their immunosuppressive characteristics may also dampen the cytokine storm that is now believed to underlie many of the manifestations of COVID-19.

Understanding their toxicity

The drugs have been approved by the US Food and Drug Administration (FDA) for emergency treatment of COVID-19. However, despite their demonstrated safety and effectiveness, these drugs may have serious side effects like diarrhea, pain in the abdomen and arrhythmias, as well as retinal damage. One study showed a higher risk of liver and kidney damage when these drugs were used in COVID-19.

The threshold above which toxicity occurs, the limit for effectiveness, and side effects must be clearly understood to achieve an optimal dosing regimen, especially for high-risk subgroups.

How was the study done?

The current study looked at eight different types of cells in culture, namely, the retina, myocardium, lung, liver, kidney, endothelium, and intestinal epithelium. These were incubated with either chloroquine or hydroxychloroquine at a range of doses (0.017 to 1000 μM) for 72 hours.

The incubating device can perform long-term imaging of dynamic cell changes, taking photographs every 3 hours, and thus inform the investigators about the pattern of cell proliferation.

The scientists also found the selectivity index SI for both drugs along with the predicted tissue concentration by the use of the physiologically-based pharmacokinetic model (PBPKM), for each target organ.

What did the results show?

The study found that hydroxychloroquine is significantly safer than chloroquine at the heart, liver, lung, and kidney. Chloroquine at over 30 μM was significantly toxic to the cells at 48 hours. Hydroxychloroquine showed significant toxicity to the cells at 100 μM at 48 hours. At over 300 μM, most cells died within 3 hours.

Comparison of the concentration at which half the cells showed cytotoxic effects at 48 and 72 hours showed that at over 300 μM of either drug, all eight cell lines showed signs of severe and rapid toxicity. The heart, kidney, and intestinal cell lines were most sensitive to chloroquine (and the first two to hydroxychloroquine too), with the concentration required to produce toxicity in half the cells being less than 20 μM.

Cumulative toxicity

The CC50 decreased over time for both drugs suggesting that the toxicity was due to drug accumulation. However, the SI of hydroxychloroquine is higher than that of chloroquine for most cell types.

Maximum tissue concentrations

The SI indicates the safe range of activity of the drug. The effective concentration at which hydroxychloroquine kills half the viral particles of SARS-CoV-2 (EC50) is less than that of chloroquine by almost eight-fold, and the CC50 is also lower.

The PBPK models showed what would happen if standard courses of the two drugs were given: hydroxychloroquine 600 mg twice a day for one day followed by 200 mg twice a day from days 2 to 5, or chloroquine 500 mg twice a day for seven days. The maximum tissue concentrations were calculated.

This showed that the highest concentrations of chloroquine resulted from the accumulation of the drug in the liver and the lung, at 3 times that of the heart. For hydroxychloroquine, the highest concentration is in the lung rather than in the liver, kidney, or heart.

They also calculated the ratio of the tissue trough concentration to the CC50 (RTTCC­) to compare the risk of toxicity of the two drugs in each tissue. They found that the R­TTCC was 6-87 times higher for chloroquine compared to hydroxychloroquine for the lung, heart, kidney, and liver.

What do the results mean?

The promising antiviral activity of chloroquine and hydroxychloroquine has led to their widespread adoption against COVID-19. However, it is important to remember that they have toxicities directed against different types of cells in the body. These toxic actions are time- and dose-dependent, which means that the drugs should be given for only a short time to prevent cumulative toxicity.

Simulation of effects on various cell types

Different cell types react differently to the drugs. For instance, liver and intestinal cell types have the greatest sensitivity to chloroquine but lung and intestine to hydroxychloroquine. The importance of the distribution of the drug is revealed as a factor affecting its toxicity. The PBPK model has shown that hydroxychloroquine has a better safety profile compared to chloroquine.

It is noteworthy that a recent report contradicts this, which might be the result of complex differences in the way the drugs behave in the living body as opposed to in vitro systems.

The use of the RTTCC allows the investigators to monitor the whole process of proliferation and to differentiate the effects on different tissues. The researchers emphasize the need to perform ECG monitoring throughout the period of usage of these drugs, even if the patient doesn’t show signs of severe disease and if the person shows symptoms of impaired vision.

The study does not give any clearcut evidence for or against the use of these drugs in COVID-19 but suggests that it adds value to their study in clinical and preclinical trials.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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