In this study, the pharmacokinetic characteristics and tissue distribution of cannabidiol(CBD)/γ-polyglutamic acid-g-cholesterol(γ-PGA-g-CHOL) nanomicelles [CBD/(γ-PGA-g-CHOL)NMs] were investigated by pharmacokinetic experiments, and the effect of CBD/(γ-PGA-g-CHOL)NMs on the lipopolysaccharide(LPS)-induced inflammatory damage of cells was evaluated by cell experiments. CBD/(γ-PGA-g-CHOL)NMs were prepared by dialysis. The CBD concentrations in the plasma samples of male SD rats treated with CBD and CBD/(γ-PGA-g-CHOL)NMs were investigated, and the pharmacokinetic parameters were calculated and compared. UPLC-MS/MS was employed to determine the concentration of CBD in tissue samples. The heart, liver, spleen, lung, kidney, and muscle samples were collected at different time points to explore the tissue distribution of CBD and CBD/(γ-PGA-g-CHOL)NMs. The Caco-2 cell model of LPS-induced inflammation was established, and the cell viability, transepithelial electrical resistance(TEER), and secretion levels of inflammatory cytokines were determined to compare the anti-inflammatory activity between the two groups. The results showed that CBD/(γ-PGA-g-CHOL)NMs had the average particle size of(163.1±2.3)nm, drug loading of 8.78%±0.28%, and encapsulation rate of 84.46%±0.35%. Compared with CBD, CBD/(γ-PGA-g-CHOL)NMs showed increased peak concentration(C_(max)) and prolonged peak time(t_(max)) and mean residence time(MRT_(0-t)). Within 24 h, the tissue distribution concentration of CBD/(γ-PGA-g-CHOL)NMs was higher than that of CBD. In addition, both CBD and CBD/(γ-PGA-g-CHOL)NMs significantly enhanced Caco-2 cell viability and TEER, lowered the secretion levels of inflammatory cytokines, and alleviated inflammation. Moreover, CBD/(γ-PGA-g-CHOL)NMs demonstrated stronger anti-inflammatory effect. It can be inferred that γ-PGA-g-CHOL blank nanomicelles are good carriers of CBD, being capable of prolonging the circulation time of CBD in the blood, improving the bioavailability and tissue distribution concentration of CBD, and protecting against LPS-induced inflammatory injury. The findings can provide an experimental basis for the development and clinical application of oral CBD preparations.
Animals ; Cannabidiol/administration & dosage* ; Polyglutamic Acid/analogs & derivatives* ; Humans ; Male ; Rats ; Rats, Sprague-Dawley ; Anti-Inflammatory Agents/administration & dosage* ; Micelles ; Caco-2 Cells ; Cholesterol/pharmacokinetics* ; Tissue Distribution ; Nanoparticles/chemistry*

Simvastatin is used to reduce plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is primarily used to treat hypercholesterolemia. This study was conducted to assess the bioequivalence between the generic formulation of simvastatin 20 mg and the branded formulation of simvastatin 20 mg. A generic formulation of simvastatin 20 mg tablet was developed and the pharmacokinetics of the generic formulation were compared with those of the branded formulation of simvastatin 20 mg tablet in 33 healthy male volunteers after a single oral dose in a randomized, open-label, two-period, two-sequence, crossover study. The reference (Zocor®, MSD Korea LTD.) and test (Simvarotin®, Korea Arlico Pharm Co., Ltd.) formulations, two 20 mg tablets each, were administered to all subjects in fasting status. The serial blood samples for pharmacokinetic analysis were collected before dosing and up to 24 hours post-dose, and plasma concentrations of simvastatin were determined by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters including T(max), C(max), AUC(last), AUC(inf) and t½ were calculated for both formulations by non-compartmental method, and the log-transformed C(max) and AUC(last) were compared statistically. Geometric mean ratios (90% confidence intervals) of the test to the reference formulation in C(max) and AUC(last) were 0.9652 (0.8302–1.1223) and 0.9891 (0.8541–1.1455), respectively. No significant differences in tolerability profiles were noted between the two formulations. The two formulations of simvastatin 20 mg tablets exhibited comparable pharmacokinetic profiles and 90% confidence intervals were within the acceptable range of bioequivalence criteria.
Cholesterol ; Coenzyme A ; Cross-Over Studies ; Fasting ; Humans ; Hypercholesterolemia ; Korea ; Male* ; Mass Spectrometry ; Methods ; Oxidoreductases ; Pharmacokinetics ; Plasma ; Simvastatin* ; Tablets ; Therapeutic Equivalency ; Volunteers*

Atorvastatin and ezetimibe are frequently co-administered to treat patients with dyslipidemia for the purpose of low-density lipoprotein cholesterol control. However, pharmacokinetic (PK) drug interaction between atorvastatin and ezetimibe has not been evaluated in Korean population. The aim of this study was to investigate PK drug interaction between two drugs in healthy Korean volunteers. An open-label, randomized, multiple-dose, three-treatment, three-period, Williams design crossover study was conducted in 36 healthy male subjects. During each period, the subjects received one of the following three treatments for seven days: atorvastatin 40 mg, ezetimibe 10 mg, or a combination of both. Blood samples were collected up to 96 h after dosing, and PK parameters of atorvastatin, 2-hydroxyatorvastatin, total ezetimibe (free ezetimibe + ezetimibe-glucuronide), and free ezetimibe were estimated by non-compartmental analysis in 32 subjects who completed the study. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of the maximum plasma concentration (C(max,ss)) and the area under the curve within a dosing interval at steady state (AUC(τ,ss)) of atorvastatin when administered with and without ezetimibe were 1.1087 (0.9799–1.2544) and 1.1154 (1.0079–1.2344), respectively. The corresponding values for total ezetimibe were 1.0005 (0.9227–1.0849) and 1.0176 (0.9465–1.0941). There was no clinically significant change in safety assessment related to either atorvastatin or ezetimibe. Co-administration of atorvastatin and ezetimibe showed similar PK and safety profile compared with each drug alone. The PK interaction between two drugs was not clinically significant in healthy Korean volunteers.
Atorvastatin Calcium* ; Cholesterol ; Cross-Over Studies ; Drug Interactions* ; Dyslipidemias ; Ezetimibe* ; Humans ; Lipoproteins ; Male ; Pharmacokinetics ; Plasma ; Volunteers*

Simvastatin reduces plasma cholesterol by inhibiting HMG-CoA reductase (HMGR) and is widely used in the treatment of hypercholesterolemia. To screening the possible genetic factors affecting the pharmacokinetics (PK) of simvastatin, 35 male Korean volunteers were enrolled from two separate bioequivalence studies. Each subject was administered 20 mg simvastatin and reference drug PK parameters were used. We used Illumina Human610Quad v1.0 DNA Analysis BeadChip for whole genome SNPs analysis and whole genome genotyping data was processed by linear regression analysis for PK parameters of drug metabolizing enzymes and transporters. We found 145 significant SNPs (P < 0.01) in C(max), 135 significant SNPs (P < 0.01) in T(max) and 85 significant SNPs (P < 0.01) in AUC(inf) from whole genome analysis. In particular, we found that the ABCC2 gene had a significant effect on C(max) and AUC(inf). These results could provide information of possible candidate genes for personalized simvastatin therapy.
Cholesterol ; DNA ; Genome ; Humans ; Hypercholesterolemia ; Linear Models ; Male ; Mass Screening* ; Oxidoreductases ; Pharmacogenetics ; Pharmacokinetics* ; Plasma ; Polymorphism, Genetic* ; Polymorphism, Single Nucleotide ; Simvastatin* ; Therapeutic Equivalency ; Volunteers

OBJECTIVES: The objective of this study is to identify alcohol pharmacokinetics and to investigate the correlations between various factors for alcohol metabolism of healthy Korean males. METHODS: The 101 recruited volunteers were randomized into two groups as one group provided 0.35 mg/mL/kg and 0.7 mg/mL/kg, the other. Blood alcohol concentration was measured and analyzed in enzymatic methods eight times from drinking point. RESULTS: Alcohol elimination rate (beta) was found to be -0.0083%/h for low dose group and -0.0157%/h for the high dose group. The results indicate discrepancy in the legal criteria of alcohol elimination rate (-0.008%/h). The measured alcohol pharmacokinetic properties were following : mean time to reach maximum alcohol concentration in blood was 30 minutes, absorption rate was 0.0197%, maximum alcohol concentration in blood was 0.4930%, and Area under the curve was 59.25. Also, alcohol elimination was not affected by age, smoking, total body water, drinking capacity, body mass index, blood cholesterol, body fat, and body fat ratio. CONCLUSION: These results suggest that legal limitation could be adjusted in Korean males. Also the research should be extended including female and senior citizens for statistical significance of the research. These findings have contributed to our knowledge of the alcohol pharmacokinetics in Korean male.
Absorption ; Adipose Tissue ; Adult* ; Body Mass Index ; Body Water ; Cholesterol ; Drinking ; Female ; Humans ; Male* ; Metabolism ; Pharmacokinetics* ; Smoke ; Smoking ; Volunteers

It is reported that polyethylene glycol-lipid (PEG-lipid) derivatives increase liposomes stability, prolong the blood circulation of liposomes, enhance their tumor-targeting efficiency, and improve drug efficacy. Therefore, it is of great importance to investigate the influence of modified PEG-lipid derivatives on the physical, chemical, and biological characteristics of liposomes for the promotion of dealing with the existed problems, such as the accelerated blood clearance (ABC) phenomenon when repeated intravous injection at a certain time-interval, and developing novel targeted pharmaceutical preparations. In this review, the effects of modified PEG-lipid derivatives were summarized in many aspects. It indicats that the chemical bonds (amide, ether, ester, and disulfide) between PEG and lipid, as well as the species of lipids, such as the commonly used phosphatidylethanolamine, cholesterol, and diacylglycerol have substantial effects on the grafted liposomes stability in vitro and in vivo. Besides, the properties of lipids (the fatty acid chain length and saturation) and the groups (methoxy, carboxylic and amino) at the distal ends of the PEG chains were also considered to be important factors. In the end, the influence of the average molecular weight of PEG and the molar ratio of PEG-lipid derivatives in the total lipid were further focused.
Cholesterol ; chemistry ; Drug Delivery Systems ; methods ; Drug Stability ; Fatty Acids ; chemistry ; Liposomes ; chemistry ; pharmacokinetics ; Phosphatidylethanolamines ; chemistry ; Polyethylene Glycols ; chemistry

OBJECTIVETo optimize the formulation and preparation process of sinomenine liposomes.

METHODMethod of aether injection and mixture uniform design were adopted to determine the formulation of sinomenine liposomes is the proportion of phospholipids, cholesterol and Vitamin E with the index of entrapment efficiency. And the single-factor test was used to study the preparation process of the liposomes, including the volume of buffer solution, the preparation temperature and the ultrasonic time.

RESULTThe optimized formulation was that the ratio of sinomenine : phospholipids : cholesterol : vitamin E mass ratio was 8.92 : 60.35 : 28.81 : 1.91. The volume of buffer solution was 50 mL x g(-1) membrane, the preparation temperature was 50 degrees C, and the ultrasonic time was 20 min.

CONCLUSIONSatisfactory shape and entrapment efficiency of the liposomes can be obtained by the optimized formulation and preparation process.

Chemistry, Pharmaceutical ; Cholesterol ; Dosage Forms ; Drug Carriers ; Drug Compounding ; economics ; methods ; Drug Delivery Systems ; Drug Stability ; Liposomes ; Morphinans ; pharmacokinetics ; Particle Size ; Phospholipids ; Technology, Pharmaceutical

This study was conducted to investigate the in vitro characteristics of cationic liposomes composed of 3beta-[N-[2-(N', N'-dimethylamino) ethyl] carbamoyl] cholesterol (DC-Chol) and dipalmitoylphosphatidylcholine loaded with doxorubicin (DXR), and to provide useful information for the in vivo tumor vascular targeting of cationic liposomes. Cationic liposomes composed of different amounts of DC-Chol (0 mol%, 10 mol%, 25 mol%, 50 mol%) were loaded with the conventional anti-cancer drug doxorubicin. Their size, zeta potential, encapsulation efficiency, and DXR release in vitro were investigated. Moreover, their uptake by rat aortic endothelial cells (RAECs) was observed at 15 min, 30 min, 1 h, and 4 h of incubation. FITC-Dextran was i.v. injected to the H22 tumor-bearing KM mice to stain the neovasculature. The characteristics of resulting DXR-loaded cationic liposomes were in stable characteristics with particle sizes around 100 - 200 nm and capsulation efficiency greater than 90%. Increased cationic lipid led to enhanced zeta potential, and meanwhile it also resulted in quick release of the loaded drug, indicating increased slits or pores on the membrane upon the addition of DC-Chol. RAECs could more avidly take up DXR-loaded cationic liposomes when the content of DC-Chol increased in the liposomes, and DXR were quickly released in the cytoplasm and transported to the nuclei. The neovasculature stained by FITC-Dextran was clearly observed. DXR-cationic liposomes composed of DC-Chol could be used for tumor vascular targeting in vivo for further study.
Animals ; Aorta ; cytology ; Cell Line, Tumor ; Cholesterol ; analogs & derivatives ; chemistry ; pharmacokinetics ; Doxorubicin ; administration & dosage ; pharmacokinetics ; Drug Carriers ; Drug Delivery Systems ; Endothelial Cells ; metabolism ; Female ; Liposomes ; chemistry ; pharmacokinetics ; Liver Neoplasms, Experimental ; pathology ; Male ; Mice ; Neovascularization, Pathologic ; metabolism ; Particle Size ; Rats ; Rats, Sprague-Dawley

Hepatocytes act as a reservoir for the human immunodeficiency viruses (HIV) and are responsible for its continual dissemination in the peripheral circulation. For this reason, galactosylated liposomes (GalLs) containing home-made [(2-lactoylamido) ethylamino] formic acid cholesterol ester (CH-ED-LA ) as a homing device were prepared to study the biodistribution of the liposomal azidothymidine palmitate (AZTP) in mice. Four liposomes of the present study, soybean phosphatidylcholine (SPC)/cholesterol(CH)/CH-ED-LA (80 : 10: 10, 10% GalLs), SPC/CH/CH-ED-LA (80 : 15:5, 5% GalLs), SPC/CH/CH-ED-LA (80 : 17 : 3, 3% GallLs) and SPC/CH (80 : 20, CL) incorporated AZTP were prepared by ethanol-injection method followed by ultrasonic-dispersion and characterized by entrapped efficiency which was more than 95% and their mean diameter was less than 100 nm, respectively. The effects of the addition upon the liposomal membrane potential and AZTP content were also unseen. The distributions of AZT in various organs were determinated by reversed phase HPLC after intravenous administration via tail vein in mice, at a dose of 15.85 mg x kg(-1) AZT solution and 30 mg x kg(-1) AZTP (at equimolar doses) in CL or GalLs, respectively. Compared to AZT control solution, the half-life of AZT in each group of AZTP liposomes increased significantly (P < 0.05). In addition, the concentration-averaged overall drug targeting efficiency (r(e)) of the liver presented by AZTP CL and GalLs containing 3% , 5% , 10% (mol/mol) CH-ED-LA increased 1.32 and 1.48, 2.13, 1.50 times as that of AZT solution, respectively. These results indicate that liposomes containing such novel galactosylated lipid, CH-ED-LA, had remarkably improved the targetability of AZTP to liver, and are anticipated to be a potential candidate for liver targeting delivery carriers.
Animals ; Anti-HIV Agents ; administration & dosage ; pharmacokinetics ; Cholesterol ; analogs & derivatives ; chemistry ; Drug Carriers ; Drug Compounding ; Drug Delivery Systems ; Female ; Injections, Intravenous ; Liposomes ; chemistry ; Liver ; metabolism ; Male ; Mice ; Palmitates ; administration & dosage ; pharmacokinetics ; Particle Size ; Random Allocation ; Tissue Distribution ; Zidovudine ; administration & dosage ; pharmacokinetics

AIMTo investigate the biodistribution and the hepatocytes targeting of cationic liposome containing 3beta[N-( N',N'-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) and surface-modified liposomes with sterylglucoside (SG) and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE).

METHODSCationic liposomes (CL) composed of DC-Chol and dipalmitoylphosphatidylcholine (DPPC), SG/PEG modified cationic liposome (SG/PEG-CL), both contained trace 3H-cholesterol (3H-Chol) as radiolabel, were prepared. The liposomes encapsulating 125I-labled antisense oligodeoxynucleotide (125I-asODN) (SG/PEG-CL-asODN) were also prepared. The biodistribution of CL, SG/PEG-CL, SG/PEG-C2-asODN as well as 125I-asODN solution, were studied. The radioactivities in hepatocytes and non-hepatocytes after administration of CL and SG/PEG-CL were determined by infuseing method.

RESULTSCL and SG/PEG CL significantly aggregated in liver. The distribution of SG/PEG CL was significantly higher in hepatocytes (P < 0.01) and lower in non-hepatocytes (P < 0.01) than that of CL. The concentrations of SG/PEG-CL-asODN in liver and spleen were significantly higher than that of asODN solution (P < 0.01).

CONCLUSIONCationic liposome modified with SG/PEG changed the distribution of asODN. Cationic liposome can target hepatocytes more effective after being modified with SG.

1,2-Dipalmitoylphosphatidylcholine ; administration & dosage ; pharmacokinetics ; Animals ; Area Under Curve ; Cholestenes ; administration & dosage ; pharmacokinetics ; Cholesterol ; administration & dosage ; analogs & derivatives ; pharmacokinetics ; Drug Carriers ; Drug Delivery Systems ; Hepatocytes ; metabolism ; Liposomes ; administration & dosage ; pharmacokinetics ; Male ; Mice ; Oligodeoxyribonucleotides, Antisense ; administration & dosage ; pharmacokinetics ; Phosphatidylethanolamines ; administration & dosage ; pharmacokinetics ; Polyethylene Glycols ; administration & dosage ; pharmacokinetics ; Tissue Distribution