Based on Chinese clinical guidance for COVID-19 pneumonia diagnosis and treatment (7^th edition), the metabolism and pharmacokinetics of drugs used in clinical treatment of COVID-19 were reviewed. The antiviral drugs include remdesivir, chloroquine/hydroxychloroquine, lopinavir/ritonavir, favipiravir, arbidol, baicalin, baicalein and forsythin. Among them, the metabolism and pharmacokinetics of arbidol, baicalin and forsythin are the research results of the author's laboratory. This article aims to provide reference for the efficacy evaluation and rational drug use of COVID-19.

The metabolism study of radiolabeled drugs plays an important role in the development of new drugs. It provides information on drug absorption, metabolism, tissue distribution and excretion, and plays an irreplaceable role in the metabolite safety evaluation and mass balance of new drugs. The new guidance draft on clinical trials of radiolabeled drugs recently released by the US FDA puts forward higher standards and has been widely concerned by the industry. In recent years, in the research and development of new drugs in China, ¹⁴C labeled drugs have been used to carry out clinical metabolism studies, which has overcome key technical bottlenecks and accumulated experience. This paper summarizes the above research progress, analyzes the existing problems, and preliminarily looks forward to the future technological development and application.

The study aims to evaluate the bioequivalence of valsartan hydrochlorothiazide tablets, and to investigate the potential cause of bioinequivalence. This was a single-center study with an open, randomized double-way crossover design. Test and reference preparations containing 160 mg of valsartan and 25 mg of hydrochlorothiazide were given to 36 healthy male volunteers. Plasma concentrations of valsartan and hydrochlorothiazide were determined simultaneously by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated, while the bioequivalence between test and reference preparations were evaluated. The dissolution profiles of test and reference preparations in four different mediums were determined via dissolution test and HPLC. The similarity was investigated according to the similarity factors (f2). The F(o-t) and F(0-infinity) were (139.4 +/- 65.2)% and (137.5 +/- 61.2)% for valsartan of test preparations. It led to get the conclusion that test and reference preparations were not bioequivalent for valsartan. A significant difference was observed between test and reference tablets in the valsartan dissolution test of pH 1.2 hydrochloric acid solution. The key factor of the bioinequivalence might be that dissolution of valsartan in acid medium has marked difference between two preparations.
Administration, Oral ; Adolescent ; Adult ; Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Antihypertensive Agents ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Area Under Curve ; Chromatography, Liquid ; Cross-Over Studies ; Drug Liberation ; Humans ; Hydrochlorothiazide ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Male ; Tablets ; Tandem Mass Spectrometry ; Therapeutic Equivalency ; Valsartan ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Young Adult

A rapid, sensitive and convenient LC-MS/MS method was developed for the determination of γ-aminobutyric acid (GABA) in human plasma. d2-γ-Aminobutyric acid (d2-GABA) was synthesized as internal standard (IS). After extraction from human plasma by protein precipitation with acetonitrile, all analytes were separated on a Luna HILIC column (100 mm x 3.0 mm, 3 μm) using an isocratic mobile phase of water: acetonitrile: formic acid (20 : 80 : 0.12) with a flow rate of 0.5 mL x min(-1). Acquisition of mass spectrometric data was performed in multiple reaction monitoring mode (MRM) in positive electrospray ionization using the transitions of m/z 104 --> 69 for GABA and m/z 106 --> 71 for d2-GABA. The method was linear in the concentration range of 5.00 to 1 000 ng x mL(-1). The intra- and inter-day precisions were within 9.9%, and accuracy ranged from 99.1% to 104%, within the acceptable limit across all concentrations. The method was successfully applied to a pharmacokinetic study of GABA tablets in healthy Chinese volunteers.
Chromatography, Liquid ; Humans ; Tandem Mass Spectrometry ; gamma-Aminobutyric Acid ; blood

Human protein tyrosine kinases play an essential role in carcinogenesis and have been recognized as promising drug targets. By the end of 2012, eight small molecule tyrosine kinase inhibitors (TKIs) have been approved by State Food and Drug Administration of China for cancer treatment. In this paper, the pharmacokinetic characteristics (absorption, distribution, metabolism and excretion) and drug-drug interactions of the approved TKIs are reviewed. Overall, these TKIs reach their peak plasma concentrations relatively fast; are extensively distributed and highly protein bound (> 90%); are primarily metabolized by CYP3A4; most are heavily influenced by CYP3A4 inhibitors or inducers except for sorafenib; are mainly excreted with feces and only a minor fraction is eliminated with the urine; and are substrate of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Additionally, many of the TKIs can inhibit some CYP450 enzymes, UGT enzymes, and transporters. Gefitinib, erlotinib, dasatinib, and sunitinib are metabolized to form reactive metabolites capable of covalently binding to biomolecules.
Antineoplastic Agents ; pharmacokinetics ; pharmacology ; Crown Ethers ; pharmacokinetics ; pharmacology ; Cytochrome P-450 Enzyme System ; metabolism ; Dasatinib ; pharmacokinetics ; pharmacology ; Drug Interactions ; Erlotinib Hydrochloride ; pharmacokinetics ; pharmacology ; Glucuronosyltransferase ; metabolism ; Humans ; Imatinib Mesylate ; pharmacokinetics ; pharmacology ; Indoles ; pharmacokinetics ; pharmacology ; Niacinamide ; analogs & derivatives ; pharmacokinetics ; pharmacology ; Phenylurea Compounds ; pharmacokinetics ; pharmacology ; Protein Kinase Inhibitors ; pharmacokinetics ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; pharmacokinetics ; pharmacology ; Pyrroles ; pharmacokinetics ; pharmacology ; Quinazolines ; pharmacokinetics ; pharmacology

The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.
Administration, Oral ; Amlodipine ; administration & dosage ; blood ; Benzazepines ; administration & dosage ; blood ; Chromatography, Liquid ; Humans ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry

AIMTo develop a sensitive, specific and accurate method for quantifying 9-nitrocamptothecin in rat plasma and tissues and to study the distribution of 9-nitrocamptothecin in rat tissues.

METHODSPlasma and tissue samples were prepared based on a simple liquid-liquid extraction and separation through a Hypersil BDS C18 column. The mobile phase for plasma samples and tissue samples consisted of a mixture of acetonitrile-water-formic acid (35:65:2) and a mixture of acetonitrile-water-formic acid (30:70:2), respectively. The UV detector was set at 370 nm.

RESULTSA linear calibration curve of 9-nitrocamptothecin in plasma was obtained in the concentration range of 25-1,600 micrograms.L-1, and the quantitation limit of plasma and tissues was 25 micrograms.L-1. A linear range of concentrations for 9-nitrocamptothecin in heart, lung, spleen, stomach, fat, womb, and ovary was 10-1,000 ng.g-1, and the quantitation limit was 10 ng.g-1. A linear range of concentrations for 9-nitrocamptothecin in brain, kidney, liver, intestine, smooth muscle, skeletal muscle, and tectical was 5-500 ng.g-1, and the quantitation limit was 5 ng.g-1. The intra- and inter-run precision was measured to be below 11%. The inter-run accuracy was less than 5% for the analyte. After i.v. administration of 9-nitrocamptothecin, the drug was distributed extensively in rat in vivo. The concentration in lung was the highest, and the drug was accumulated in lung and liver. Following ig administration, the concentration in stomach was higher than that in other organs.

CONCLUSIONThe method is shown to be accurate and convenient, and suitable for preclinical pharmacokinetic studies of 9-nitrocamptothecin.

Animals ; Antineoplastic Agents, Phytogenic ; blood ; pharmacokinetics ; Camptothecin ; analogs & derivatives ; blood ; pharmacokinetics ; Chromatography, High Pressure Liquid ; Female ; Liver ; metabolism ; Lung ; metabolism ; Male ; Rats ; Rats, Wistar ; Tissue Distribution

To study the metabolite excretion of theophylline, a rapid and specific method by liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) method for simultaneous determination of theophylline, 1, 3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX) and 1-methyluric acid (1-MU) in human urine was developed using theophylline-d6 and 5-fluorouracil as internal standards. Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the negative mode for mass spectrometric detection. After diluted with methanol and centrifuged, the analytes and ISs were separated on a XDB-Phenyl (150 mm x 4.6 mm, 5 microm) column with a mixture of water-methanol-formic acid (30 : 70 : 0.15) as mobile phase at a flow rate of 0.6 mL x min(-1). The linear calibration curves for theophylline, 1, 3-DMU, 3-MX and 1-MU were obtained in the concentration range of 1.0-250 microg x mL(-1), separately. The method herein described is effective and convenient, and can be used for determination of theophylline and its three metabolites. The results showed that urinary excretion ratio of theophylline, 1,3-DMU, 3-MX and 1-MU is approximately 1 : 3 : 1 : 2 in Chinese subjects, which is similar to the reported excretion pattern in Caucasian.
Administration, Oral ; Asian Continental Ancestry Group ; Calibration ; Chromatography, Liquid ; Delayed-Action Preparations ; metabolism ; Healthy Volunteers ; Humans ; Spectrometry, Mass, Electrospray Ionization ; Tablets ; Tandem Mass Spectrometry ; Theophylline ; metabolism ; urine ; Uric Acid ; analogs & derivatives ; urine ; Xanthines ; urine

Biological Products ; analysis ; pharmacology ; Chromatography, Liquid ; methods ; Drug Evaluation, Preclinical ; methods ; Gas Chromatography-Mass Spectrometry ; methods ; Magnetic Resonance Spectroscopy ; Plants, Medicinal ; chemistry

AIM:To investigate whether Smad pathway participates the process of extracellular signal regulated kinase (ERK) induced the proliferation of vascular smooth muscle cells (VSMCs). METHODS: Human umbilical artery smooth muscle cells (hUASMCs) were divided into four groups: control group, PDGF (platelet derived growth factor) group, ERK blocking agent group and PDGF+ERK blocking agent group. MTT assay was used to detect the proliferation of hUASMCs (A value). Immunohistochemical technique was used to detect the expression of PCNA, phosphorylated ERK (p-ERK) and phosphorylated Smad2/3 (p-Smad2/3) protein in hUASMCs. The expression of Smad2/3 mRNA in hUASMCs was detected by RT-PCR. RESULTS: The proliferation of hUASMCs and the expression of PCNA, p-ERK and p-Smad2/3 proteins in hUASMCs in PDGF group were increased obviously than those in other groups (P