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Single Oral Administration (single + oral_administration)
Selected AbstractsEmodin, a natural product, selectively inhibits 11,-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese miceBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010Ying Feng BACKGROUND AND PURPOSE 11,-Hydroxysteroid dehydrogenase type 1 (11,-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11,-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice. EXPERIMENTAL APPROACH Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11,-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice. KEY RESULTS Emodin is a potent and selective 11,-HSD1 inhibitor with the IC50 of 186 and 86 nM for human and mouse 11,-HSD1, respectively. Single oral administration of emodin inhibited 11,-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11,-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA. CONCLUSIONS AND IMPLICATIONS This study demonstrated a new role for emodin as a potent and selective inhibitor of 11,-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes. [source] Pharmacokinetics of dipeptidylpeptidase-4 inhibitorsDIABETES OBESITY & METABOLISM, Issue 8 2010A. J. Scheen Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase-4 (DPP-4) inhibitors are new oral glucose-lowering agents, so-called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed-dose combined formulations with metformin. Other DPP-4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP-4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle-aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half-life and sustained DPP-4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice-daily administration is recommended because of a shorter half-life. DPP-4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP-4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP-4 inhibitors suggest that these compounds are not exposed to a high risk of drug,drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose-lowering effect without inducing hypoglycaemia or weight gain, DPP-4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice. [source] A physiologically based pharmacokinetic model for endosulfan in the male Sprague-Dawley ratsENVIRONMENTAL TOXICOLOGY, Issue 5 2006Melissa P. L. Chan Abstract Endosulfan, an organochlorine (OC) insecticide belonging to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. To date, no physiologically based pharmacokinetic (PBPK) model has been located for endosulfan in animal species and humans. The estimation by a mathematical model is essential since information on humans can scarcely be obtained experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of 14C-Endosulfan to male Sprague-Dawley rats. The model was parameterized by using reference physiological parameter values and partition coefficients that were determined in the experiment and optimized by manual adjustment until the best visual fit of the simulations with the experimental data were observed. The model was verified by simulating the disposition of 14C-Endosulfan in vivo after single and multiple oral dosages and comparing simulated results with experimental results. The model was further verified by using experimental data retrieved from the literature. The present model could reasonably predict target tissue dosimetries in rats. Simulation with three-time repeated administration of 14C-Endosulfan and experimental data retrieved from the literature by the constructed model fitted fairly well with the experimental results; thus suggesting that the newly developed PBPK model was developed. Sensitivity analyses were used to determine those input parameters with the greatest influence on endosulfan tissue concentrations. © 2006 Wiley Periodicals, Inc. Environ Toxicol 21: 464,478, 2006. [source] Tissue distribution of antihypertensive dipeptide, Val-Tyr, after its single oral administration to spontaneously hypertensive ratsJOURNAL OF PEPTIDE SCIENCE, Issue 9 2004Toshiro Matsui Abstract The distribution of an antihypertensive dipeptide, Val-Tyr (VY), in the tissues of spontaneously hypertensive rats (SHR) was investigated in this study. A single oral administration of VY (10 mg/kg) to 18-week-old SHR resulted in a prolonged reduction of systolic blood pressure (SBP) up to 9 h (SBP0h198.0 ± 3.6 mmHg; SBP9h 154.6 ± 3.5 mmHg). As a result of VY determination, a roughly 10-fold higher increment of plasma VY level was observed at 1 h than that at 0 h, whereas thereafter the level declined rapidly. In tissues, VY was widely accumulated in the kidney, lung, heart, mesenteric artery and abdominal aorta with the area under the curve over 9 h of more than 40 pmol h/g tissue; of these a higher VY level was observed in the kidney and lung. In addition, a mean resident time (MRT) for each tissue (>5 h except for liver) revealed that VY preferably accumulated in the tissues rather than in the plasma (MRT 3.8 h). Significant reductions of tissue angiotensin I-converting enzyme activity and angiotensin II level were found in the abdominal aorta as well as in the kidney, suggesting that these organs could be a target site associated with the antihypertensive action of VY. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd. [source] Physiologically based predictions of the impact of inhibition of intestinal and hepatic metabolism on human pharmacokinetics of CYP3A substratesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2010Frederique Fenneteau Abstract The first objective of the present study was to predict the pharmacokinetics of selected CYP3A substrates administered at a single oral dose to human. The second objective was to predict pharmacokinetics of the selected drugs in presence of inhibitors of the intestinal and/or hepatic CYP3A activity. We developed a whole-body physiologically based pharmacokinetics (WB-PBPK) model accounting for presystemic elimination of midazolam (MDZ), alprazolam (APZ), triazolam (TRZ), and simvastatin (SMV). The model also accounted for concomitant administration of the above-mentioned drugs with CYP3A inhibitors, namely ketoconazole (KTZ), itraconazole (ITZ), diltiazem (DTZ), saquinavir (SQV), and a furanocoumarin contained in grape-fruit juice (GFJ), namely 6,,7,-dihydroxybergamottin (DHB). Model predictions were compared to published clinical data. An uncertainty analysis was performed to account for the variability and uncertainty of model parameters when predicting the model outcomes. We also briefly report on the results of our efforts to develop a global sensitivity analysis and its application to the current WB-PBPK model. Considering the current criterion for a successful prediction, judged satisfied once the clinical data are captured within the 5th and 95th percentiles of the predicted concentration,time profiles, a successful prediction has been obtained for a single oral administration of MDZ and SMV. For APZ and TRZ, however, a slight deviation toward the 95th percentile was observed especially for Cmax but, overall, the in vivo profiles were well captured by the PBPK model. Moreover, the impact of DHB-mediated inhibition on the extent of intestinal pre-systemic elimination of MDZ and SMV has been accurately predicted by the proposed PBPK model. For concomitant administrations of MDZ and ITZ, APZ and KTZ, as well as SMV and DTZ, the in vivo concentration,time profiles were accurately captured by the model. A slight deviation was observed for SMV when coadministered with ITZ, whereas more important deviations have been obtained between the model predictions and in vivo concentration,time profiles of MDZ coadministered with SQV. The same observation was made for TRZ when administered with KTZ. Most of the pharmacokinetic parameters predicted by the PBPK model were successfully predicted within a two-fold error range either in the absence or presence of metabolism-based inhibition. Overall, the present study demonstrated the ability of the PBPK model to predict DDI of CYP3A substrates with promising accuracy. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:486,514, 2010 [source] ,-cyclodextrin reduces bioavailability of orally administered [3H]benzo[a]pyrene in the ratJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2005Goran Westerberg Abstract The excretion and plasma kinetics of total radioactivity were studied following single oral administration of [3H]benzo[a]pyrene after multiple oral administration of ,-cyclodextrin at 0, 5, 50, or 500 mg/kg/day. The AUC and Cmax values in male and female rats following administration of [3H]benzo[a]pyrene in combination with 5 to 500 mg/kg ,-cyclodextrin were considerably lower than that in rats administered [3H]benzo[a]pyrene alone. At all dose levels of ,-cyclodextrin, the excretion of total radioactivity was almost entirely via feces, with <2% recovered in urine, demonstrating either that absorption of the orally administered dose was low or that, for any absorbed material, biliary excretion was the main route of excretion. However, following administration of vehicle, up to 5% of the administered radioactivity was recovered in the urine, suggesting that absorption may have been reduced by the presence of ,-cyclodextrin in the intestine. At all dose levels of ,-cyclodextrin, there was minimal retention of radioactivity in the carcase at the end of the collection period. ,-Cyclodextrin did not affect the apparent terminal half-life of radioactivity. Therefore, the reduced systemic exposure of rats to radioactivity in the presence of ,-cyclodextrin is likely related to a reduced oral bioavailability. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:114,119, 2005 [source] The use of three different solid dispersion formulations,melt extrusion, film-coated beads, and a glass thermoplastic system,to improve the bioavailability of a novel microsomal triglyceride transfer protein inhibitorJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2004Geert Verreck Abstract A bioavailable formulation for a water-insoluble microsomal triglyceride transfer protein inhibitor, R103757, was developed using solid dispersion technology. The need for an advanced formulation was tested in the dog by assessing the oral bioavailability of three generic concepts: a tablet (crystalline drug), a capsule (film-coated beads), and an oral solution. These screening studies steered further development in the direction of a solid dispersion. Three solid dispersion platforms were assessed: melt extrusion, film-coated beads, and a glass thermoplastic system. Thermal and spectrophotometric analysis revealed that no crystalline drug was present in any of the formulations. The dissolution profiles of the three dispersion systems showed that release was improved compared with the unmanipulated drug. In addition, stability studies confirmed the physical and chemical integrity of the formulation. A human clinical trial was performed to assess the pharmacokinetics of the three amorphous dispersions. Plasma levels were obtained after single oral administration in both the fasting and fed state. The study indicated that all three approaches improved the bioavailability of R103757 with the glass thermoplastic system providing the best performance. These studies point to the potential usefulness of solid dispersion approaches and expand the possible number of ways to implement these methodologies. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1217,1228, 2004 [source] Toxicokinetics and recovery studies of dicamba dimethyl amine salt in goats following single oral administrationJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 2 2010Madhusudan Mukherjee Abstract BACKGROUND: Toxicokinetics and recovery studies of dicamba dimethyl amine salt (DDAS) were conducted to obtain more information about its toxicity and tissue retention in farm animals. RESULTS: The minimum oral toxic dose level of DDAS was determined as 1400 mg kg,1 body weight. In the toxicokinetic study, blood DDAS concentration of 55.6 ± 0.59 µg mL,1 (mean ± standard error) was detected at 0.08 h, which peaked to 102.3 ± 5.03 µg mL,1 at 0.25 h, and declined to a minimum of 4.1 ± 0.06 µg mL,1 at 36 h. In recovery studies, DDAS concentration in urine began to increase significantly (P < 0.05) from 12 h, peaked at 24 h and declined from 48 h onwards. Maximum excretion through faeces was at 24 h and was complete by 144 h. The residual level in tissues decreased significantly (P < 0.05) on day 7 as compared to day 4. In histopathological studies, cellular alterations in lungs, liver, kidney, adrenal gland and spleen were found. CONCLUSION: DDAS persists in the body for a shorter period and its major excretory route is through urine. DDAS has lower affinity to accumulate in tissues, and intensity of cellular alterations is not severe after single-dose oral administration. Copyright © 2009 Society of Chemical Industry [source] Pharmacokinetics of Dietary 13C-Labeled Docosahexaenoic Acid and Docosapentaenoic Acid in Red Sea Bream Chrysophrys majorJOURNAL OF THE WORLD AQUACULTURE SOCIETY, Issue 2 2002Akio Tago The objectives of this study were to investigate: 1) the pharmacokinetics of dietary docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) using 13C-labeled fatty acids; 2) the interorgan transport of DHA in the red sea bream by monitoring the DHA level of several organs; and 3) the relationship between the plasma DHA level and optimum dietary DHA level in the plasma of the red sea bream Chrysophrys major. For this purpose, a mixture of 38.5% of [13C]DHA, 8.5% of [13C]DPA, and 4.2% of [13C]palmitic acid were given to the red sea bream at dose level of 8.0, 16.0, and 47.9 mg/kg by a single oral administration. For [13C]DHA, the maximum plasma concentration (tmax) occurred at 2.00,3.00 h after the oral administration. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve to 24 h (AUC0-24 for [13C]DHA level linearly increased with respect to dosage. [13C]DHA appeared in each organ (plasma, erythrocyte and the fat body of the orbit, liver, intestine, skin, brain, heart and muscle) at 0.5 h and was observed until 24 h. From the values determined for the pharmacokinetic parameters, the range of the effective plasma DHA level for normal growth of the red sea bream was suggested to be between 21.0 and 40.3 ,g/mL. For [13C]DPA, the AUC0-24 and Cmax values also linearly increased with the dosage, but tmax did not depend on it. [source] Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tabletsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2009G. LE TRAON Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment (tmax = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed (tmax = 2.25 h) and decreased the rate and extent of absorption (AUC) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs. [source] Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodiumJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2008G. LE TRAON Oral l -thyroxine (l -T4) supplementation is used to replace thyroid hormone concentrations in dogs with hypothyroidism. The pharmacokinetics of l -T4 following administration of a solution (Leventa®) was investigated in healthy dogs. l -T4 was absorbed fairly rapidly (tmax 3 h). A mean bioavailability of 22% was calculated following a single oral administration of 40 ,g l -T4/kg body weight. Repeated oral administration at the same dose for 14 consecutive days did not lead to any accumulation of T4 in serum. After intravenous administration of l -T4, a serum half-life of 11.6 h was calculated. Food intake concomitant with l -T4 oral administration delayed l -T4 absorption and decreased its rate and extent by about 45%. The relative bioavailability of l -T4 following administration of a tablet formulation was about 50% of that of the l -T4 solution. The pharmacokinetic properties of liquid l -T4 after oral administration support the use of a dose rate of 20 ,g/kg once daily, as a starting dose for replacement therapy in dogs with hypothyroidism. [source] Comparative serum pharmacokinetics of the fluoroquinolones enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single oral administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2002E. HEINEN The pharmacokinetics after oral application of the fluoroquinolones (FQs), enrofloxacin, difloxacin, marbofloxacin and orbifloxacin were compared in independent crossover studies in Beagle dogs. Commercially available tablet formulations were given at common dosage recommended by the manufacturers which were 2.0 mg/kg body weight (bw) for marbofloxacin, 2.5 mg/kg bw for orbifloxacin and 5.0 mg/kg bw for enrofloxacin and difloxacin. Analysis was performed by an agar diffusion assay. Pharmacokinetic parameters were calculated by noncompartmental methods. All FQs were rapidly absorbed and achieved average peak serum concentrations of 1.41, 1.11, 1.47 and 1.37 ,g/mL for enrofloxacin, difloxacin, marbofloxacin and orbifloxacin, respectively. Enrofloxacin was eliminated at a terminal half-life (t½) of 4.1 h, difloxacin at 6.9 h, orbifloxacin at 7.1 h and marbofloxacin at 9.1 h. While the area under the serum concentration,time curve of the 24-h dosing interval (AUC0,24) for marbofloxacin and orbifloxacin were similar (approximately 13 ,g · h/mL), enrofloxacin attained an AUC0,24 of 8.7 and difloxacin of 9.3 ,g · h/mL. Because of its favourable pharmacokinetics combined with excellent in vitro activity, enrofloxacin exhibited superior pharmacodynamic predictors of in vivo antimicrobial activity as Cmax/MIC (maximum serum concentration/minimum inhibitory concentration) and AUC0,24/MIC (area under the 24-h serum concentration,time curve/minimum inhibitory concentration) compared with other FQs. [source] Inhibitory effect of magnolol on Trp-P-2-induced DNA damage in various organs in micePHYTOTHERAPY RESEARCH, Issue 7 2009Junichiro Saito Abstract Magnolol has been reported to strongly inhibit the mutagenicity induced by indirect mutagens in the Ames test as well as the clastogenicity induced by benzo(a)pyrene (B(a)P) in the mice micronucleus test. Here, we evaluated the inhibitory effect of magnolol on the DNA damage induced by 3-amino-1-methyl-5H -pyrido[4,3-b]indole (Trp-P-2) in various organs using the mice alkaline single cell gel electrophoresis (SCG) assay. Animals were treated with a single oral administration of magnolol (0.01, 0.1, 1, 10, and 100 mg/kg), followed by a single intraperitoneal injection of Trp-P-2 (10 mg/kg). The liver, lung, and kidney were removed at 3 h after treatment and used in SCG assay. The results indicated that magnolol inhibited Trp-P-2-induced DNA damage in various organs. To elucidate the mechanism of this inhibitory effect against Trp-P-2, we investigated the inhibitory effect of magnolol on in vivo CYP1A2 activity using the zoxazolamine paralysis test. Magnolol significantly prolonged zoxazolamine paralysis time and showed an inhibitory effect on in vivo CYP1A2 activity. These results indicate that magnolol has an inhibitory effect on the DNA damage induced by Trp-P-2 in various organs in vivo. This inhibitory mechanism is considered due to in vivo CYP1A2 inhibition. Copyright © 2009 John Wiley & Sons, Ltd. [source] Hypoglycemic effect and chlorogenic acid content in two Cecropia speciesPHYTOTHERAPY RESEARCH, Issue 8 2005Pilar Nicasio Abstract The hypoglycemic effect of methanol leaf extracts from Cecropia obtusifolia and C. peltata was evaluated in healthy mice. A significant decrease (p < 0.05) in plasma glucose levels was recorded 2 and 4 h after a single oral administration of methanol extracts (1 g/kg). This effect was correlated with the chlorogenic acid contents in both species; C. peltata, containing 19.84 ± 1.64 mg of chlorogenic acid/g of dried leaves produced the highest decrease (D, 2,60 = 20.18, p < 0.05) of plasma glucose levels (52.8%). The extracts of C. obtusifolia from Tabasco and Veracruz, showed similar hypoglycemic effects (33.3% and 35.7%, respectively) and chlorogenic acid contents (Tukey0.05 = 1.8859) (13.3 ± 3.2 mg/g and 13.1 ± 1.6 mg/g, respectively). The hypoglycemic effect produced by different doses (0.1, 0.25, 0.50, 0.75 and 1 g/kg body wt, p.o.) of C. peltata showed a lineal relationship with chlorogenic acid content, reaching an ED50 = 0.540 g/kg body wt for extract, and an ED50 = 10.8 mg/kg body wt for chlorogenic acid. These results suggest that C. peltata is a better hypoglycemic agent than C. obtusifolia, and it could be considered for developing a phytomedicinal product to carry out clinical trials. Copyright © 2005 John Wiley & Sons, Ltd. [source] Development and validation of a liquid chromatographic/tandem mass spectrometric method for the determination of sertraline in human plasmaRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 16 2006Xiaoyan Chen A sensitive and rapid liquid chromatographic/tandem mass spectrometric method was developed and validated for the determination of sertraline in human plasma. The analyte and internal standard (IS, diphenhydramine) were extracted with 3,mL of diethyl ether/dichloromethane (2:1, v/v) from 0.25,mL plasma, then separated on a Zorbax Eclipse XDB C18 column using methanol/water/formic acid (75:25:0.1, v/v/v) as the mobile phase. The triple quadrupole mass spectrometry was applied via an atmospheric pressure chemical ionization (APCI) source for detection. The fragmentation pattern of the protonated sertraline was elucidated with the aid of product mass spectra of isotopologous peaks. Quantification was performed using selected reaction monitoring of the transitions of m/z 306,,,159 for sertraline and m/z 256,,,167 for the IS. The method was linear over the concentration range of 0.10,100,ng/mL. The intra-day and inter-day precisions, expressed by relative standard deviation, were both less than 6.7%. Assay accuracies were within ±6.9% as terms of relative error. The lower limit of quantification (LLOQ) was identifiable and reproducible at 0.10,ng/mL with a precision of 8.3% and an accuracy of 9.6%. The validated method has been successfully applied for the pharmacokinetic study and bioequivalence evaluation of sertraline in 18 healthy volunteers after a single oral administration of 50,mg sertraline hydrochloride tablets. Copyright © 2006 John Wiley & Sons, Ltd. [source] Di(n -butyl) Phthalate Induces Vimentin Filaments Disruption in Rat Sertoli Cells: A Possible Relation with Spermatogenic Cell ApoptosisANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 3 2010M. S. Alam With 3 figures Summary Phthalate esters have been extensively used as a plasticizer of synthetic polymers. Previous studies have revealed that some phthalate esters including di(n -butyl) phthalate (DBP) induce spermatogenic cell apoptosis, although its mechanism is not yet clear. The present study describes that disruption of Sertoli cell vimentin filaments by DBP administration may relate to spermatogenic cell apoptosis. The present histopathological study revealed that a single oral administration of 500 mg/kg DBP caused progressive detachment and displacement of spermatogenic cells away from the seminiferous epithelium and sloughing of them into the lumen. Degenerative spermatogenic cells characterized by chromatin condensation were frequently observed in DBP-treated rats. Ultrastructurally, the degenerative spermatogenic cells were separated from their neighbours, and a collapse of Sertoli cell vimentin filaments was recognized in DBP-treated rats. Sertoli cell cultures showed the increased number and size of vacuoles in their cytoplasm. In agreement with the in vivo experiment, vimentin filaments clearly showed a gradual collapse in DBP-exposed Sertoli cells in vitro. These in vivo and in vitro experiments indicate that DBP-induced collapse of Sertoli cell vimentin filaments may lead to detachment of spermatogenic cells, and then detached cells may undergo apoptosis because of loss of the support and nurture provided by Sertoli cells. [source] Liquid chromatographic/mass spectrometry assay of bromotetrandrine in rat plasma and its application to pharmacokinetic studyBIOMEDICAL CHROMATOGRAPHY, Issue 6 2009Naining Song Abstract A rapid and sensitive liquid chromatography,tandem mass spectrometric method (LC-MS/MS) for the determination of bromotetrandrine in rat plasma has been developed and applied to pharmacokinetic study in Sprague,Dawley (SD) rats after a single oral administration. Sample preparation involves a liquid,liquid extraction with n -hexane,dichlormethane (65:35, containing 1% 2-propanol isopropyl alcohol, v/v). Bromotetrandrine and brodimoprim (internal standard, IS) were well separated by LC with a Dikma C18 column using methanol,ammonium formate aqueous solution (20 mm) containing 0.5% formic acid (60:40, v/v) as mobile phase. Detection was performed on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. The ionization was optimized using ESI(+) and selectivity was achieved using MS/MS analysis, m/z 703.0 , 461.0 and m/z 339.0 , 281.0 for bromotetrandrine and IS, respectively. The present method exhibited good linearity over the concentration range of 20,5000 ng/mL for bromotetrandrine in rat plasma with a lower limit of quantification of 20 ng/mL. The intra- and inter-day precisions were 2.8,7.5% and 3.2,8.1%, and the intra- and inter-day accuracy ranged from ,4.8 to 8.2% and ,5.6 to 6.2%, respectively. The method was successfully applied to a pharmacokinetic study after a single oral administration to SD rats with bromotetrandrine of 50 mg/kg. Copyright © 2009 John Wiley & Sons, Ltd. [source] Liquid chromatography with electrospray ionization mass spectrometry method for the assay of glucosamine sulfate in human plasma: validation and application to a pharmacokinetic studyBIOMEDICAL CHROMATOGRAPHY, Issue 3 2006Tao-Min Huang Abstract A liquid chromatography,electrospray ionization mass spectrometry (LC,ESI,MS) method was developed and validated for the assay of glucosamine sulfate in human plasma. Plasma proteins were precipitated by acetonitrile, followed by vortex mixing and centrifugation. The supernatant was transferred and derivatized with phenyl iso-thiocyanate in acetonitrile at 60°C for 40 min. Chromatographic separation was performed on a C18 column (Inertsil ODS-3 150 × 2.1 mm i.d., 5 µm, JP) with a mobile phase gradient consisting of 0.2% acetic acid (aqueous) and methanol at a flow-rate of 0.3 mL/min. MS detection using electrospray ionization (ESI) as an interface was used in single ion monitoring mode to determine positive ions at m/z 297. This method was shown to be selective and sensitive for glucosamine sulfate. The limit of detection was 35 ng/mL for glucosamine sulfate in plasma and the linear range was 0.1,20 µg/mL in plasma with a correlation coefficient (r) of 0.9991. The relative standard deviations (RSDs) of intra-day and inter-day assays were 8.7,11.4 and 9.8,12.6%, respectively. Extraction recoveries of glucosamine sulfate in plasma were greater than 73%. This method proved to be simple, reproducible and feasible for pharmacokinetic studies of glucosamine sulfate in healthy volunteers after a single oral administration (1500 mg). The pharmacokinetic parameters and relative bioavailabilities were investigated for both domestic glucosamine sulfate tablet and capsule preparations compared with an imported capsule product. Copyright © 2005 John Wiley & Sons, Ltd. [source] Pharmacokinetics and metabolism of neferine in rats after a single oral administrationBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2007Ying Huang Abstract The present study utilized HPLC and LC-MS approaches to investigate the pharmacokinetics and metabolism of neferine (a bisbenzylisoquinoline alkaloid). The plasma concentration-time curves of neferine (10, 20 and 50 mg/kg, i.g.) showed double absorption peaks with the first peak at 10 min and the second peak at 1 h. The t was 15.6 h, 22.9 h and 35.5 h, for each of these doses, respectively. Neferine distributed rapidly into different organ systems, with the highest concentrations found in the liver, followed by the lung, kidney and heart at doses of 10 or 20 mg/kg. At 50 mg/kg dose, concentrations of the kidney and lung were higher than those of others. Moreover, this compound was mainly metabolized in the liver and converted partially by CYP2D6 to liensinine, isoliensinine, desmethyl-liensinine and desmethyl-isoliensinine. Copyright © 2007 John Wiley & Sons, Ltd. [source] Absorption, distribution, metabolism and excretion of YM466, a novel factor Xa inhibitor, in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2004Yuji Mano YM466 is a novel factor Xa inhibitor for the treatment of thrombosis. The absorption, distribution, metabolism and excretion of YM466 were investigated in male Fisher rats after a single oral administration. YM466 was absorbed rapidly from all segments of the gastrointestinal tract except the stomach. After oral dosing, the plasma concentration of 14C-YM466 reached a maximum within 0.5h, and declined rapidly with an elimination half-life of 0.64h. The unchanged YM466 accounted for almost all of its radioactivity, suggesting a minimal metabolism in rats. This was also supported by the finding that no metabolites were observed in bile and urine after oral dosing of 14C-YM466. The distribution of 14C-YM466 in tissue was evaluated and the liver and kidney were the organs with radioactivity concentrations consistently higher than that of plasma. Cumulative biliary and urinary excretion of radioactivity in bile duct-cannulated rats was 29.5% and 7.6%, respectively, indicating prominent excretion into bile after oral dosing. This was consistent with the finding that 76.1% and 25.2% of radioactivity dosed were excreted to faeces and urine, respectively, after i.v. dosing. These results suggest that YM466 was rapidly absorbed and then subjected to biliary excretion with a minimal metabolism after oral dosing to rats. Copyright © 2004 John Wiley & Sons, Ltd. [source] Complete bioavailability and lack of food-effect on pharmacokinetics of gliclazide 30 mg modified release in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2002P. Delrat Abstract A new modified release (MR) formulation containing 30 mg of gliclazide was developed to obtain a better predictable release of the active principle and to allow once-daily dosing regimen. An absolute bioavailability study was carried out to characterise the performance of the new formulation and the food-effect was also investigated in a separate study. Both studies were single dose, randomised, open label, two way cross over studies with a wash out period between doses. For the bioavailability study, each volunteer received 30 mg of gliclazide given either as a 1 h intravenous infusion or as a 30 mg MR tablet. For the food-effect study, the treatment was given either fasted or 10 min after the start of a standardised Melander breakfast. Blood samples were collected up to 72 h after administrations and plasma samples assayed for gliclazide concentrations using a reverse-phase HPLC method with UV detection. Mean absolute bioavailability of gliclazide was 97% and ranged between 79 and 110% showing complete absorption. A similar moderate to low variability was observed after IV and oral administration showing the MR formulation did not add to the overall variability which is solely due to the disposition parameters, in particular metabolism of gliclazide. No significant difference was observed in tmax, t1/2z, Cmax and AUC of gliclazide after administration of the 30 mg MR tablet under fasted and fed conditions. In conclusion, after single oral administration of a 30 mg MR tablet, gliclazide was completely absorbed both under fasted and fed conditions. A consistent and optimal release of gliclazide from this formulation leads to a low to moderate overall variability of its pharmacokinetic parameters. Diamicron 30 mg MR can be given without regards to meals i.e. before, during or after breakfast. Copyright © 2002 John Wiley & Sons, Ltd. [source] Subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, after single and 4-week repeated oral administration in dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2001Hyun J. Shim Abstract The subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, were evaluated after single (at the 1st day) and 4-week (at the 28th day) oral administration of the drug, in doses of 0 (to serve as a control), 12.5, 50 and 200 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). DA-8159 had an effect on the immune-related organs (or tissues), circulatory systems, liver, adrenal glands, ovaries and pancreas. The toxic dose was 200 mg/kg and no observed adverse effect level was less than 50 mg/kg for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of DA-8159 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DA-8159 were dose-independent after single oral administration; the time to reach a peak plasma concentration (Tmax) and the dose-normalized area under the plasma concentration,time curve from time zero to 24 h in plasma (AUC0,24 h) were not significantly different among three doses. However, accumulation of DA-8159 after 4-week oral administration was considerable at toxic dose, 200 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC0,24 h value at 200 mg/kg/day (4.71 and 15.3 ,g h/ml) was significantly greater than that at 12.5 mg/kg/day. After 4-week oral administration, the dose-normalized Cmax and AUC0,24 h at 200 mg/kg/day were significantly higher and greater, respectively, than those after a single oral administration. Copyright © 2001 John Wiley & Sons, Ltd. [source] Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2001Michael G. Hall Aims NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. Methods A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Results Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg kg,1 body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (± s.d.) AUC(0,,) (capsule 602 ± 154 vs solution 602 ± 146 µg ml,1 h) or t½ (capsule 55 ± 13 vs solution 54 ± 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,,) and Cmax increased linearly with dose. Following administration of 1 mg NTBC kg,1 in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol ml,1. Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol ml,1 following a dose of 4 mg kg,1 body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione kg,1, but returned to background levels during the following 24 h period. Conclusions NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use. [source] | ||||||||||||||||