Abstract
Hydroxychloroquine (HCQ) was originally used as an antimalarial and immunomodulation drug. We developed and validated a simple and sensitive ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous quantitation of HCQ and its three metabolites in rat blood, and reported their pharmacokinetic parameters. The chromatographic separation and detection of analytes were achieved within 4 min on ZORBAX SB-C8 (3.5 μm, 2.1 × 150 mm) column with gradient elution, and the flow rate was 0.25 mL/min. Simple protein precipitation was successfully applied for sample pretreatment. The HCQ displays a good linearity in the range of 2.0–5000.0 ng/mL, and the three metabolites also show good linearity ranging from 1.0 to 2500.0 ng/mL, with all correlation coefficients (R2) better than 0.98. In conclusion, this rapid, sensitive method was successfully developed, validated, and then applied to a pharmacokinetic study of HCQ in rat model in high dose. The results of the pharmacokinetic study presented an average half-life time 21.14 ± 10.31 h (mean ± SD) of HCQ, which is much shorter in human compared to that in mice. For the three metabolites, longer half-life times (approximately 100 h) were shown in rat.
Highlights
IntroductionRecent in vitro studies had confirmed that HCQ and CQ have antiviral activity against SARS-CoV-2 virus and that the efficacy of HCQ is better than that of CQ (EC50, 0.72 vs 5.47 μmol/L), but many clinical studies had reported that HCQ was ineffective in human body for Covid-19 [2,3,4,5,6,7,8,9,10]
Hydroxychloroquine (HCQ), an antimalarial drug, is the hydroxyl-substituted product of chloroquine (CQ), which has become the backstone in the treatment of rheumatic arthritis (RA) and systemic lupus erythematosus (SLE) in recent years because of its characteristics of immunomodulatory, hypolipidemic, antithrombotic effect, and, the HCQ was utilized to reduce the risk of malignant tumors and treat sarcoidosis and still disease [1]
HCQ is metabolized into three active metabolites, that is, bisdesethylchloroquine (BDCQ), desethylchloroquine (DCQ), and desethylhydroxychloroquine (DHCQ) [11] in the liver by CYP 450 enzymes. e CYP 450 enzymes play critical roles in the catabolism of HCQ, which are mainly mediated by some subtypes such as CYP3A4, CYP3A5, CYP2D6, and CYP2C8 and the gene polymorphisms of them affect the blood concentrations of HCQ and three metabolites [12]
Summary
Recent in vitro studies had confirmed that HCQ and CQ have antiviral activity against SARS-CoV-2 virus and that the efficacy of HCQ is better than that of CQ (EC50, 0.72 vs 5.47 μmol/L), but many clinical studies had reported that HCQ was ineffective in human body for Covid-19 [2,3,4,5,6,7,8,9,10] In these studies, the HCQ was administered in different doses (200–1200 mg) and in different frequencies (once a day to three times a day) for several days (4–21 days), and these regimens (high dose and multiple administrations) differ greatly from the HCQ prescription in SLE and RA treatment. Chhonker et al [13]. reported the pharmacokinetic parameters of HCQ after intravenous injection of 5 mg/kg HCQ in mice: t1/2 12.7 ± 1.1 h, AUC0–∞ 5577.8 ± 881.8 ng h/mL, and AUC0–72 5490.6 ± 890.0 ng h/mL. e half-life time of HCQ in mice is much shorter than that in human. ese results make the therapeutic drug monitoring and pharmacokinetic study of high-dose HCQ necessary
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