1.Pharmacokinetic interactions between the potential COVID-19 treatment drugs lopinavir/ritonavir and arbidol in rats.
Yunzhen HU ; Minjuan ZUO ; Xiaojuan WANG ; Rongrong WANG ; Lu LI ; Xiaoyang LU ; Saiping JIANG
Journal of Zhejiang University. Science. B 2021;22(7):599-602
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has occasioned worldwide alarm. Globally, the number of reported confirmed cases has exceeded 84.3 million as of this writing (January 2, 2021). Since there are no targeted therapies for COVID-19, the current focus is the repurposing of drugs approved for other uses. In some clinical trials, antiviral drugs such as remdesivir (Grein et al., 2020), lopinavir/ritonavir (LPV/r) (Cao et al., 2020), chloroquine (Gao et al., 2020), hydroxychloroquine (Gautret et al., 2020), arbidol (Wang et al., 2020), and favipiravir (Cai et al., 2020b) have shown efficacy in COVID-19 patients. LPV/r combined with arbidol, which is the basic regimen in some regional hospitals in China including Zhejiiang Province, has shown antiviral effects in COVID-19 patients (Guo et al., 2020; Xu et al., 2020). A retrospective cohort study also reported that this combination therapy showed better efficacy than LPV/r alone for the treatment of COVID-19 patients (Deng et al., 2020).
Animals
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COVID-19/drug therapy*
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Drug Interactions
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Drug Therapy, Combination
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Female
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Indoles/pharmacokinetics*
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Lopinavir/pharmacokinetics*
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Male
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Rats
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Retrospective Studies
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Ritonavir/pharmacokinetics*
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SARS-CoV-2
2.Metabolism of 3-cyanomethyl-4-methyl-DCK, a new anti-HIV candidate, in human intestinal microsomes.
Xiao-mei ZHUANG ; Yuan-yuan WEN ; Hua LI ; Jing-ting DENG ; Wei-li KONG ; Xing-tao TIAN ; Shu-li CUI ; Lan XIE
Acta Pharmaceutica Sinica 2010;45(9):1116-1122
The biotransformation, CYP reaction phenotyping, the impact of CYP inhibitors and enzyme kinetics of 3-cyanomethyl-4-methyl-DCK (CMDCK), a new anti-HIV preclinical candidate belonging to DCK analogs, were investigated in human intestinal microsomes and recombinant cytochrome P450 (CYP) enzymes. CMDCK (4 micromol L(-1)) was incubated with a panel of rCYP enzymes (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The remaining parent drug in incubates was quantitatively analyzed by a LC-MS method. CYP3A4 was identified as the principal CYP isoenzyme responsible for its metabolism in intestinal microsomes. The major metabolic pathway of CMDCK was oxidation and a number of oxidative metabolites were screened with LC-MS. The Km, Vmax, CLint and T1/2 of CMDCK obtained from human intestinal microsome were 45.6 micromol L(-1), 0.33 micromol L(-1) min(-1), 12.1 mL min(-1) kg(-1) and 25.7 min, respectively. Intestinal clearance of CMDCK was estimated from in vitro data to be 3.3 mL min(-1) kg(-1), and was almost equal to the intestinal blood flow rate (4.6 mL min(-1) kg(-1)). The selective CYP3A4 inhibitors, ketoconazole, troleandomycin and ritonavir demonstrated significant inhibitory effects on CMDCK intestinal metabolism, which suggested that co-administration of CMDCK with potent CYP3A inhibitors, such as ritonavir, might decrease its intestinal metabolic clearance and subsequently improve its bioavailability in body.
Anti-HIV Agents
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metabolism
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pharmacokinetics
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Biological Availability
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Bridged Bicyclo Compounds, Heterocyclic
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metabolism
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pharmacokinetics
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Coumarins
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metabolism
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pharmacokinetics
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors
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Humans
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Intestines
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metabolism
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Ketoconazole
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pharmacology
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Metabolic Clearance Rate
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Microsomes
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metabolism
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Ritonavir
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pharmacology
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Troleandomycin
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pharmacology