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1.
Biomed Pharmacother ; 151: 113124, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1850707

ABSTRACT

The substrate-analog furin inhibitor MI-1851 can suppress the cleavage of SARS-CoV-2 spike protein and consequently produces significant antiviral effect on infected human airway epithelial cells. In this study, the interaction of inhibitor MI-1851 was examined with human serum albumin using fluorescence spectroscopy and ultrafiltration techniques. Furthermore, the impacts of MI-1851 on human microsomal hepatic cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 activities were assessed based on fluorometric assays. The inhibitory action was also examined on human recombinant CYP3A4 enzyme and on hepatocytes. In addition, microsomal stability (60 min) and cytotoxicity were tested as well. MI-1851 showed no relevant interaction with human serum albumin and was significantly depleted by human microsomes. Furthermore, it did not inhibit CYP1A2, 2C9, 2C19 and 2D6 enzymes. In human hepatocytes, CYP3A4 was significantly suppressed by MI-1851 and weak inhibition was noticed in regard to human microsomes and human recombinant CYP3A4. Finally, MI-1851 did not impair the viability and the oxidative status of primary human hepatocytes (up to 100 µM concentration). Based on these observations, furin inhibitor MI-1851 appears to be potential drug candidates in the treatment of COVID-19, due to the involvement of furin in S protein priming and thus activation of the pandemic SARS-CoV-2.


Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Furin , Albumins/pharmacology , COVID-19/drug therapy , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme Inhibitors/metabolism , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme Inhibitors/toxicity , Cytochrome P-450 Enzyme System/drug effects , Cytochrome P-450 Enzyme System/metabolism , Furin/antagonists & inhibitors , Furin/metabolism , Furin/pharmacology , Humans , Microsomes, Liver , SARS-CoV-2/drug effects , Serum Albumin, Human/metabolism , Spike Glycoprotein, Coronavirus
2.
Drug Metab Dispos ; 50(5): 576-590, 2022 05.
Article in English | MEDLINE | ID: covidwho-1832315

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), was recently granted emergency use authorization by multiple regulatory agencies for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients. Disposition studies on nirmatrelvir in animals and in human reagents, which were used to support clinical studies, are described herein. Plasma clearance was moderate in rats (27.2 ml/min per kg) and monkeys (17.1 ml/min per kg), resulting in half-lives of 5.1 and 0.8 hours, respectively. The corresponding oral bioavailability was moderate in rats (34%-50%) and low in monkeys (8.5%), primarily due to oxidative metabolism along the gastrointestinal tract in this species. Nirmatrelvir demonstrated moderate plasma protein binding in rats, monkeys, and humans with mean unbound fractions ranging from 0.310 to 0.478. The metabolism of nirmatrelvir was qualitatively similar in liver microsomes and hepatocytes from rats, monkeys, and humans; prominent metabolites arose via cytochrome P450 (CYP450)-mediated oxidations on the P1 pyrrolidinone ring, P2 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, and the tertiary-butyl group at the P3 position. Reaction phenotyping studies in human liver microsomes revealed that CYP3A4 was primarily responsible (fraction metabolized = 0.99) for the oxidative metabolism of nirmatrelvir. Minor clearance mechanisms involving renal and biliary excretion of unchanged nirmatrelvir were also noted in animals and in sandwich-cultured human hepatocytes. Nirmatrelvir was a reversible and time-dependent inhibitor as well as inducer of CYP3A activity in vitro. First-in-human pharmacokinetic studies have demonstrated a considerable boost in the oral systemic exposure of nirmatrelvir upon coadministration with the CYP3A4 inhibitor ritonavir, consistent with the predominant role of CYP3A4 in nirmatrelvir metabolism. SIGNIFICANCE STATEMENT: The manuscript describes the preclinical disposition, metabolism, and drug-drug interaction potential of PF-07321332 (nirmatrelvir), an orally active peptidomimetic-based inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease, which has been granted emergency use authorization by multiple regulatory agencies around the globe for the treatment of coronavirus disease 2019 (COVID-19) in COVID-19-positive adults and pediatric patients who are at high risk for progression to severe COVID-19, including hospitalization or death.


Subject(s)
COVID-19 , SARS-CoV-2 , Administration, Oral , Animals , COVID-19/drug therapy , Child , Cytochrome P-450 CYP3A/metabolism , Haplorhini , Humans , Lactams , Leucine , Microsomes, Liver/metabolism , Nitriles , Peptide Hydrolases/metabolism , Proline , Rats , Ritonavir/metabolism
3.
Clin Pharmacol Ther ; 111(6): 1324-1333, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1802136

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor-tezacaftor-ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A-mediated DDI of elexacaftor-tezacaftor-ivacaftor was evaluated using a physiologically-based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug-dependent parameters of elexacaftor-tezacaftor-ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor-tezacaftor-ivacaftor. The elexacaftor-tezacaftor-ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor-tezacaftor-ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor-tezacaftor-ivacaftor should be reduced when coadministered with nirmatrelvir-ritonavir to elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full-dose elexacaftor-tezacaftor-ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of elexacaftor-tezacaftor-ivacaftor administered concomitantly with nirmatrelvir-ritonavir in people with CF that will likely decrease the impact of the drug interaction.


Subject(s)
COVID-19 , Cystic Fibrosis , Aminophenols/pharmacology , Benzodioxoles/pharmacology , COVID-19/drug therapy , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator , Cytochrome P-450 CYP3A/metabolism , Drug Combinations , Drug Interactions , Humans , Indoles/pharmacology , Lactams/pharmacokinetics , Leucine/pharmacokinetics , Mutation , Nitriles/pharmacokinetics , Proline/pharmacokinetics , Pyrazoles/pharmacology , Pyridines/pharmacology , Pyrrolidines , Quinolines/pharmacology , Quinolones , Ritonavir/pharmacokinetics
4.
Molecules ; 27(3)2022 Jan 29.
Article in English | MEDLINE | ID: covidwho-1667252

ABSTRACT

Aspirin (also known as acetylsalicylic acid) is a drug intended to treat fever, pain, or inflammation. Treatment of moderate to severe cases of COVID-19 using aspirin along with dexamethasone has gained major attention globally in recent times. Thus, the purpose of this study was to use High-Performance Liquid Chromatography (HPLC) to evaluate the in vitro inhibition of CYP3A2 enzyme activity using aspirin in rat liver microsomes (RLMs). In this study, an efficient and sensitive HPLC method was developed using a reversed phase C18 column (X Bridge 4.6 mm × 150 mm, 3.5 µm) at 243 nm using acetonitrile and water (70:30 v/v). The linearity (r2 > 0.999), precision (<15%), accuracy and recovery (80-120%), limit of detection (5.60 µM and 0.06 µM), limit of quantification (16.98 µM and 0.19 µM), and stability of the newly developed method were validated for dexamethasone and 6ß-hydroxydexamethasone, respectively, following International Conference on Harmonization (ICH) guidelines. This method was applied in vitro to measure CYP3A2 activity. The results showed that aspirin competitively inhibits 6ß-hydroxylation (CYP3A2 activity) with an inhibition constant (Ki) = 95.46 µM and the concentration of the inhibitor causing 50% inhibition of original enzyme activity (IC50) = 190.92 µM. This indicated that there is a minimal risk of toxicity when dexamethasone and aspirin are co-administrated and a very low risk of toxicity and drug interaction with drugs that are a substrate for CYP3A2 in healthcare settings.


Subject(s)
Aspirin/pharmacology , Chromatography, High Pressure Liquid/methods , Cytochrome P-450 CYP3A/metabolism , Animals , Aspirin/chemistry , COVID-19/drug therapy , Cytochrome P-450 CYP3A/drug effects , Cytochrome P-450 Enzyme Inhibitors/metabolism , Cytochrome P-450 Enzyme System/metabolism , Dexamethasone/analogs & derivatives , Dexamethasone/pharmacology , Male , Microsomes, Liver/metabolism , Pharmaceutical Preparations/metabolism , Protein Isoforms/metabolism , Rats , Rats, Sprague-Dawley , Reproducibility of Results , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity
5.
Biol Pharm Bull ; 44(11): 1617-1634, 2021.
Article in English | MEDLINE | ID: covidwho-1551286

ABSTRACT

The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Animals , COVID-19/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Humans , Liver Diseases/metabolism , Protein Isoforms/metabolism
6.
Clin Pharmacol Ther ; 111(3): 579-584, 2022 03.
Article in English | MEDLINE | ID: covidwho-1396859

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) may experience a cytokine storm with elevated interleukin-6 (IL-6) levels in response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). IL-6 suppresses hepatic enzymes, including CYP3A; however, the effect on drug exposure and drug-drug interaction magnitudes of the cytokine storm and resulting elevated IL-6 levels have not been characterized in patients with COVID-19. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate the effect of inflammation on the pharmacokinetics of CYP3A metabolized drugs. A PBPK model was developed for lopinavir boosted with ritonavir (LPV/r), using clinically observed data from people living with HIV (PLWH). The inhibition of CYPs by IL-6 was implemented by a semimechanistic suppression model and verified against clinical data from patients with COVID-19, treated with LPV/r. Subsequently, the verified model was used to simulate the effect of various clinically observed IL-6 levels on the exposure of LPV/r and midazolam, a CYP3A model drug. Clinically observed LPV/r concentrations in PLWH and patients with COVID-19 were predicted within the 95% confidence interval of the simulation results, demonstrating its predictive capability. Simulations indicated a twofold higher LPV exposure in patients with COVID-19 compared with PLWH, whereas ritonavir exposure was predicted to be comparable. Varying IL-6 levels under COVID-19 had only a marginal effect on LPV/r pharmacokinetics according to our model. Simulations showed that a cytokine storm increased the exposure of the CYP3A paradigm substrate midazolam by 40%. Our simulations suggest that CYP3A metabolism is altered in patients with COVID-19 having increased cytokine release. Caution is required when prescribing narrow therapeutic index drugs particularly in the presence of strong CYP3A inhibitors.


Subject(s)
COVID-19/complications , Cytochrome P-450 CYP3A/metabolism , Cytokine Release Syndrome/virology , Lopinavir/pharmacokinetics , Midazolam/pharmacokinetics , Ritonavir/pharmacokinetics , Adult , COVID-19/drug therapy , COVID-19/metabolism , Cytochrome P-450 CYP3A/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/metabolism , Cytokines/metabolism , Humans , Metabolic Clearance Rate/drug effects , Middle Aged , Models, Biological
7.
Food Chem Toxicol ; 149: 111998, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1139497

ABSTRACT

Corona Virus Disease 2019 (COVID-19) has spread all over the world and brings significantly negative effects on human health. To fight against COVID-19 in a more efficient way, drug-drug or drug-herb combinations are frequently used in clinical settings. The concomitant use of multiple medications may trigger clinically relevant drug/herb-drug interactions. This study aims to assay the inhibitory potentials of Qingfei Paidu decoction (QPD, a Chinese medicine compound formula recommended for combating COVID-19 in China) against human drug-metabolizing enzymes and to assess the pharmacokinetic interactions in vivo. The results demonstrated that QPD dose-dependently inhibited CYPs1A, 2A6, 2C8, 2C9, 2C19, 2D6 and 2E1 but inhibited CYP3A in a time- and NADPH-dependent manner. In vivo test showed that QPD prolonged the half-life of lopinavir (a CYP3A substrate-drug) by 1.40-fold and increased the AUC of lopinavir by 2.04-fold, when QPD (6 g/kg) was co-administrated with lopinavir (160 mg/kg) to rats. Further investigation revealed that Fructus Aurantii Immaturus (Zhishi) in QPD caused significant loss of CYP3A activity in NADPH-generating system. Collectively, our findings revealed that QPD potently inactivated CYP3A and significantly modulated the pharmacokinetics of CYP3A substrate-drugs, which would be very helpful for the patients and clinicians to avoid potential drug-interaction risks in COVID-19 treatment.


Subject(s)
COVID-19/drug therapy , Cytochrome P-450 CYP3A/metabolism , Drugs, Chinese Herbal/pharmacology , Herb-Drug Interactions , Animals , Area Under Curve , China , Drugs, Chinese Herbal/therapeutic use , Lopinavir/pharmacokinetics , Male , Microsomes, Liver , NADP/metabolism , Phytotherapy , Rats, Sprague-Dawley , SARS-CoV-2
8.
Expert Rev Vaccines ; 20(5): 623-634, 2021 05.
Article in English | MEDLINE | ID: covidwho-1118865

ABSTRACT

OBJECTIVE: Infectious disease emergencies like the 2013-2016 Ebola epidemic and the 2009 influenza and current SARS-CoV-2 pandemics illustrate that vaccines are now given to diverse populations with preexisting pathologies requiring pharmacological management. Many natural biomolecules (steroid hormones, fatty acids, vitamins) and ~60% of prescribed medications are processed by hepatic cytochrome P450 (CYP) 3A4. The objective of this work was to determine the impact of infection and vaccines on drug metabolism. METHODS: The impact of an adenovirus-based vaccine expressing Ebola glycoprotein (AdEBO) and H1N1 and H3N2 influenza viruses on hepatic CYP 3A4 and associated nuclear receptors was evaluated in human hepatocytes (HC-04 cells) and in mice. RESULTS: CYP3A activity was suppressed by 55% in mice 24 h after administration of mouse-adapted H1N1, while ˂10% activity remained in HC-04 cells after infection with H1N1 and H3N2 due to global suppression of cellular translation capacity, indicated by reduction (70%, H1N1, 56%, H3N2) of phosphorylated eukaryotic translation initiation factor 4e (eIF4E). AdEBO suppressed CYP3A activity in vivo (44%) and in vitro (26%) 24 hours after infection. CONCLUSION: As the clinical evaluation of vaccines for SARS-CoV-2 and other global pathogens rise, studies to evaluate the impact of new vaccines and emerging pathogens on CYP3A4 and other metabolic enzymes are warranted to avoid therapeutic failures that could further compromise the public health during infectious disease emergencies.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Hepatocytes/enzymology , Hepatocytes/metabolism , Liver/enzymology , Liver/metabolism , Pharmaceutical Preparations/metabolism , Animals , Cells, Cultured , Eukaryotic Initiation Factor-4E , Humans , Immunization/methods , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
9.
Chem Biol Interact ; 338: 109428, 2021 Apr 01.
Article in English | MEDLINE | ID: covidwho-1103757

ABSTRACT

Camostat mesylate, a potent inhibitor of the human transmembrane protease, serine 2 (TMPRSS2), is currently under investigation for its effectiveness in COVID-19 patients. For its safe application, the risks of camostat mesylate to induce pharmacokinetic drug-drug interactions with co-administered drugs should be known. We therefore tested in vitro the potential inhibition of important efflux (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2)), and uptake transporters (organic anion transporting polypeptides OATP1B1, OATP1B3, OATP2B1) by camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA). Transporter inhibition was evaluated using fluorescent probe substrates in transporter over-expressing cell lines and compared to the respective parental cell lines. Moreover, possible mRNA induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) was analysed in LS180 cells by quantitative real-time PCR. The results of our study for the first time demonstrated that camostat mesylate and GBPA do not relevantly inhibit P-gp, BCRP, OATP1B1 or OATP1B3. Only OATP2B1 was profoundly inhibited by GBPA with an IC50 of 11 µM. Induction experiments in LS180 cells excluded induction of PXR-regulated genes such as cytochrome P450 3A4 (CYP3A4) and ABCB1 and AhR-regulated genes such as CYP1A1 and CYP1A2 by camostat mesylate and GBPA. Together with the summary of product characteristics of camostat mesylate indicating no inhibition of CYP1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, our data suggest a low potential of camostat mesylate to act as a perpetrator in pharmacokinetic drug-drug interactions. Only inhibition of OATP2B1 by GBPA warrants further investigation.


Subject(s)
Drug Interactions , Esters/metabolism , Guanidines/metabolism , Serine Proteinase Inhibitors/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Cell Line , Cell Survival/drug effects , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Esters/chemistry , Esters/pharmacology , Guanidines/chemistry , Guanidines/pharmacology , Humans , Organic Anion Transporters/antagonists & inhibitors , Organic Anion Transporters/metabolism , Pregnane X Receptor/genetics , Pregnane X Receptor/metabolism , RNA, Messenger/metabolism , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology
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