BACKGROUND: The purpose of this study was to determine the adequate loading and maintenance doses of N-acetylcyseteine (NAC) for patients suffering from acute ROS-induced injury. METHODS: Concentrations of extra cellular NAC, cysteine (Cys), cystine (Cyst2), and methionine (Met) were measured in vitro, at which more than 50% of the intracellular ROS raised by paraquat were suppressed using Swiss 3T3 fibroblasts. An in vivo pharmacokinetic study followed on a healthy subject to determine the proper loading and maintenance doses of reduced NAC following intravenous administration of 25 mg/kg NAC. RESULTS: In vivo, NAC suppressed ROS in a dose dependant manner. 10 mM of NAC suppressed about 50% of ROS, and was comparable to 10 micro M of Cys and Met and 400 micro M of Cys2. In vitro, the elimination of half-life was achieved at 2.88+/-1.14 h for NAC and at 3.68+/-1.84 h for total NAC. The body clearances were 1.23+/-0.77 L h (-1) kg (-1) and 0.56+/-0.27 L h (-1) kg (-1) and the volumes of distribution were 3.07+/-0.10 L kg (-1) and 3.00+/-0.11 L kg (-1), respectively. The loading and maintenance NAC doses used to reach the target concentration of 10 mM, were 5010 mg. kg (-1) and 2250 mg min (-1) kg (-1), respectively. CONCLUSION: NAC provides an antioxidant effect on ROS produced by paraquat in vivo. However, in vitro, our results showed that the intravenous NAC dose could not be estimated from NAC plasma concentration or its metabolites.
Sulfur/*blood ; Reactive Oxygen Species ; Humans ; Glutathione/blood ; Amino Acids/*blood/chemistry ; Acetylcysteine/*administration & dosage/pharmacokinetics/pharmacology

Lycopene liposomes were prepared by conventional rotary-evaporated film-ultrasonication method. The release of lycopene from lycopene liposome was evaluated in vitro. The pharmacokinetic parameters of lycopene liposomes (L-LYC) and lycopene (LYC) oil, the effect of LYC and L-LYC on antioxidation were also investigated in rats. HPLC method was used to assay the concentration of lycopene in rat's plasma. Pharmacokinetic parameters were estimated by 3P97 program. The release of L-LYC and LYC were measured in the artificial stomach liquid and bowel liquid. After 4 weeks of L-LYC or LYC feeding, the activity of SOD, T-AOC, GSH-Px, MDA and CAT in serum and liver were measured separately. The pharmacokinetic parameters of LYC oil and L-LYC in a single dose were 4.45 and 7.45 h for Tmax; 0.473 and 0.654 microg x mL(-1) for Cmax; 12.38 and 21.67 mirog x h x mL(-1) for AUC,respectively. The activities of GSH-Px and T-AOC in serum and liver of the L-LYC group increased (P < 0.05) and the concentrations of MDA and CAT decreased significantly (P < 0.05). It could be concluded that lycopene liposomes could prolong the time of absorption. L-LYC could increase antioxidative effect and reduce lipid peroxidation obviously compared with LYC in rats.
Administration, Oral ; Animals ; Antioxidants ; administration & dosage ; pharmacokinetics ; Area Under Curve ; Carotenoids ; administration & dosage ; pharmacokinetics ; Catalase ; blood ; metabolism ; Chromatography, High Pressure Liquid ; methods ; Drug Carriers ; Glutathione Peroxidase ; blood ; metabolism ; Lipid Peroxidation ; drug effects ; Liposomes ; chemistry ; Liver ; metabolism ; Male ; Malondialdehyde ; blood ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; blood ; metabolism

To determine the loading and maintenance dosage of glutathione (GSH) for patients suffering from reactive oxygen species (ROS) injury such as acute paraquat intoxication, a kinetic study of reduced GSH was performed in synchrony with that of cysteine (Cys), cystine (Cys2), and methionine (Met). Human subject's porticipitation was voluntary. The effective dose of Cys, Cys2, and Met against ROS in fibroblast cells generated by paraquat was assessed using laser scanning confocal microscopy. Both Cys and Met suppressed ROS in a dose-dependent manner at concentrations of 1-1,000 micrometer; the concentration required to suppress ROS by 50% was 10 micrometer for Cys and 50 micrometer for Met. Using metabolite kinetics with the assumption that Cys and Met are the metabolites of GSH, expected concentrations of Cys and Met of above 20 and 50 micrometer were estimated when GSH was administered at 50 mg/kg body weights every 205.4 min for Cys and 427.4 min for Met.
Adult ; Amino Acids/*blood ; Animals ; Dose-Response Relationship, Drug ; Glutathione/administration and dosage/*blood/*pharmacokinetics ; Humans ; Kinetics ; Male ; Metabolic Clearance Rate/drug effects ; Mice ; Reactive Oxygen Species/*metabolism ; Research Support, Non-U.S. Gov't ; Swiss 3T3 Cells

Chlorogenic acid (5-CQA) is one of the major components in some Chinese herbal injections. However, the metabolism of 5-CQA in rats after intravenous injection has not been determined. An ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) method was applied to identify the metabolites in bile, urine, feces and plasma after a single intravenous administration of 10 mg x kg(-1) 5-CQA to rats. Using MSE and mass defect filter techniques, a total of 35 metabolites were detected in bile, urine, feces and plasma. The predominant metabolites in bile were glutathione conjugates of O-methyl-5-CQA, accounting for approximately 80% of the metabolites excreted in bile. The major components in urine were parent drug, O-methyl-5-CQA, hydrolyzed metabolites and glucuronide conjugates. The major components in feces were O-methyl-5-CQA and its cysteine conjugates. The major component in plasma was the parent drug. The urinary and fecal excretion pathways were equally important to 5-CQA in rats. These results demonstrate that 5-CQA undergoes extensively metabolism in rats and are highly reactive to nucleophiles such as GSH. This finding indicates that attention should be paid on the injections containing 5-CQA, which may covalently bind to proteins, leading to allergenic drug reactions.
Animals ; Bile ; metabolism ; Biotransformation ; Chlorogenic Acid ; administration & dosage ; blood ; pharmacokinetics ; urine ; Chromatography, High Pressure Liquid ; methods ; Cysteine ; metabolism ; Feces ; chemistry ; Glucuronides ; metabolism ; Glutathione ; metabolism ; Injections, Intravenous ; Male ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; methods