Distribution of Hydroxychloroquine in Lymphoid Tissue in a Rabbit Model for HIV Infection

Abstract

Hydroxychloroquine has been proposed for HIV treatment; however, little is known about its disposition in the lymphatic system, where replication takes place. Therefore, its distribution in lymphoid tissues (Peyer's patches and popliteal, submandibular, femoral, splenic, and prescapular lymph nodes) was evaluated and compared with that in blood. Results showed a high affinity of hydroxychloroquine for all of these tissues, with higher affinity for the splenic and submandibular lymph nodes, suggesting its potential use as a coadjuvant in HIV therapy. Hydroxychloroquine is a 4-aminoquinoline drug with more than 70 years of use as an antimalarial agent. Besides its antimalarial activity, it has well-documented efficacy and long-term safety in the therapy of autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus (1-3). The immunomodulatory effects of this agent are related to the reduction of inflammatory cytokine and IgG production, as well as down modulation of natural killer cell activity (4, 5). With regard to its in vivo anti-HIV-1 activity, it has been reported that hydroxychloroquine increases CD4ϩ T cell levels in HIV-infected patients who do not respond to antiretroviral therapy (6).Although different studies have been performed to determine its blood/plasma distribution, as well as its pharmacokinetic parameters (7, 8), little is known about its disposition in lymphoid tissue; this distribution is important since lymph nodes are the major reservoir of HIV and the primary site of HIV replication (9). In a previous study, we found that in humans, hydroxychloroquine concentrations are higher in adenoid tissue than in plasma (10); therefore, the main objective of the present study was to determine the distribution of the drug in different lymphoid tissues by using the rabbit as an experimental model, taking into account that different studies have suggested that the rabbit immune system is more similar to the immune systems of primates and humans than is that of mice (11,12,13).Healthy male New Zealand rabbits (Harlan, Mexico City, Mexico) 2 to 3 months old with a mean body weight of 2.4 kg were used. Each rabbit received a subcutaneous hydroxychloroquine (Sanofi Aventis) injection of 15 mg/kg of body weight. Blood samples were taken at 0, 10,20, 30, 60, 120, 180, 240, 360, 480, and 840 min after drug administration (three animals per time point were used). Once the blood sample was taken, the animals were killed by cervical dislocation, cessation of circulation was confirmed, and tissue samples (Peyer's patches and popliteal, submandibular, femoral, prescapular, and splenic lymph nodes) were collected in preweighed vials on the same schedule as blood samples. The minced tissues were homogenized with 1 ml of 0.1 M phosphate buffer, pH 2.5. All samples were stored at Ϫ20 Ϯ 1°C until use.The study protocol complied with the Guide to the Care and Use of Experimental Animals and was approved by the Animal Ethics Committee of the Universidad Nacional Autónoma de México.Hydroxychloroquine was...

Recent Clinical and Preclinical Studies of Hydroxychloroquine on RNA Viruses and Chronic Diseases: A Systematic Review

“…After taking these dosages, it was demonstrated that the mean HCQ concentration was significantly higher in At than in plasma [ 21 ]. This different drug distribution was also confirmed by an in vivo study using rabbits as an experimental model, receiving 15 mg/kg of HCQ subcutaneously [ 22 ]. Thus, the anti-HIV activity of HCQ could be linked to its accumulation in lymphoid tissue, a relevant site for HIV immunopathogenesis and replication.…”

Implant delivering hydroxychloroquine attenuates vaginal T lymphocyte activation and inflammation

“…As a result, it is possible that the introduced N9 gel in the current study may contribute to the increased HCQ accumulation in the DC and PC portions of the rabbit vagina by absorbing the released HCQ and evenly spreading the cervicovaginal lumen. The use of a topical delivery system in the current study and the reported short half-life of HCQ in rabbit blood (10.6 hr) [28] may be some of the reasons that HCQ is undetectable in the blood.…”

“…100 µL of HCQ mobile phase was used to reconstitute the content in the vial and 80 µL was injected for HPLC analysis. HCQ in rabbit vaginal tissue or blood was first extracted and then analyzed by RP-HPLC using a modified extraction technique as previously reported [28]. Briefly, 500 ± 50 mg of rabbit vaginal tissue (UV, DC, and PC portions) were weighed in a 1.5 mL microcentrifuge tube with the addition of 400 µL of 3 mg/mL collagenase in water.…”

A review on possible modes of action of chloroquine/hydroxychloroquine: repurposing against SAR-CoV-2 (COVID-19) pandemic

“…CQ analogues have strong affinities to blood constituents and are highly protein-bound, particularly to thrombocytes and granulocytes, which reduces its plasma concentration. In addition, a major fraction of CQ analogues in plasma is bound to plasma proteins, primarily albumin [23][24][25] .…”