bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid
Authors: Hadad Salim , Vree Tom B. , Van Der Kleijn Eppo , Bialer Meir 
Published: October 2006

AbstractThe pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4‐butanediol divaiproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4‐butanediol.
A method for calculating the mean absorption time of drugs undergoing reversible and first‐pass metabolism
Authors: Cheng Haiyung , Shum Linyee 
Published: October 2006

AbstractA method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.
Inhibition of acetaminophen and lorazepam glucuronidation in vitro by probenecid
Authors: Von Moltke Lisa L. , Manis Melanie , Harmatz Jerold S. , Poorman Roger , Greenblatt David J. 
Published: October 2006

AbstractThe effect of probenecid on glucuronidation of acetaminophen and lorazepam in hepatic microsomes from various species was studied to see if in vitro results were consistent with previous in vivo observations. Mouse, rat, and human microsomes were incubated with acetaminophen and probenecid while monkey microsomes were incubated with lorazepam and probenecid. Glucuronidation rates in all species varied with substrate, protein, and detergent concentrations. Mice exhibited faster rates of glucuronidation than rats or humans. All species showed inhibition of glucuronidation of acetaminophen or lorazepam when probenecid was added. Analysis suggested competitive inhibition. Thus, in vitro studies support in vivo results and confirm that the inhibition takes place at the hepatic level.
Human dolasetron pharmacokinetics: II Absorption and disposition following single‐dose oral administration to normal male subjects
Authors: Boxenbaum Harold , Gillespie Todd , Heck Kathleen , Hahne William 
Published: October 2006

AbstractDolasetron is a 5‐hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapyinduced nausea and vomiting. A previous study demonstrated that following intravenous administration to healthy male subjects, dolasetron disappeared extremely rapidly from plasma, and less than 1 per cent of the dose appeared in the urine. A major plasma metabolite, reduced dolasetron, peaked rapidly in the plasma. In this study, dolasetron was administered orally to healthy male subjects at doses ranging from 50 to 400 mg (mesylate monohydrate). Plasma concentrations of dolasetron were low and sporadic, and there was little excreted in urine; this prevented dolasetron pharmacokinetic analysis. Reduced metabolite concentrations peaked rapidly, with a median value of 1.00 h. The median terminal disposition half‐life was 7.80 h. Median values for fraction of dose excreted in urine and renal clearance were 22.2 per cent and 2.56 ml min−1 kg−1. Whereas areas under the plasma concentration—time curves were proportional to dose, renal clearance increased with dose (p < 0.05). However, given dose proportionality to AUC, this is probably of little therapeutic consequence. Since reduced dolasetron has significant anti‐emetic activity in the ferret model, it appears that this metabolite may play a significant role in pharmacodynamic activity.
Pharmacokinetics of D‐propranolol following oral, intra‐arterial and intraportal administration: Contrasting effects of oral glucose pretreatment
Authors: Chow Hsiao‐Hui , Lalka David 
Published: October 2006

AbstractSeveral research groups have reported that in man the oral administration of propranolol with food leads to a marked increase (about 50 per cent) in the area under the plasma concentration—time curve (AUCpo) of this well absorbed and highly metabolized drug. An acute change in hepatic metabolic enzyme activity has been postulated as one of the mechanisms which could be responsible for this observed ‘food effect’. The administration of simple carbohydrates such as glucose and fructose has been documented to influence hepatic drug metabolism. Therefore, in the present study, the effect of oral glucose (4 g kg−1 as a 50 per cent aqueous solution) on the disposition kinetics of d‐propranolol was examined in male Sprague‐Dawley rats (8 to 9 per group).Oral glucose treatment caused a statistically significant decrease (504 ± 12.3 vs 36.6 ± 15.2 min μg ml−1; p < 0.05) in the AUCpo of propranolol when this drug was given by oral intubation (10 mg kg−1). This glucose treatment also caused the apparent mean residence time of propranolol after an oral dose to increase from 0.70 ± 0.08 h to 1.79 ± 0.29 h (p < 0.05), but did not change its rate of elimination (suggesting collectively a decreased apparent intrinsic clearance and prolonged drug absorption). In a second study, the same oral glucose treatment was demonstrated to have little impact on the steady state concentrations of propranolol when this drug was infused intraarterially at a constant rate. This confirms that the systemic clearance of propranolol is influenced minimally by the glucose treatment. In a third study, propranolol was infused at a constant rate into the portal vein (pyloric vein infusion) bypassing the processes of intestinal metabolism and absorption (i.e. to remove these sources of variability associated with oral administration). Under these conditions, no significant changes in AUC or apparent mean residence time were observed for the two propranolol doses studied (10 mg kg−1 and 5 mg kg−1). We conclude that the oral glucose and oral propranolol interaction appears to be due to an alteration in the input process before drug enters the liver. Furthermore, this experimental series suggests that studies combining accurate assessments of systemic clearance (constant rate intra‐arterial infusion studies), intrnsic hepatc clearance (pyloric en infusion studies), ad oral administration supplemented wth necessary protein binding studies may be used together to charenterize te mechanism responsible for drug‐nutrient and drug‐drug interactions.
Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of bumetanide
Authors: Ryoo Si H. , Lee Myung G. , Lee Min H. 
Published: October 2006

AbstractThe pharmacokinetics and pharmacodynamics of bumetanide were evaluated after intravenous (i.v.) administration of the same total dose of bumetanide in different lengths of infusion times, 10 s (treatment I), 1 h (treatment II), and 4 h (treatment III) to rabbits. The fluid loss in urine was immediately replaced volume for volume with i.v. infusion of lactated Ringer's solution. Some pharmacokinetic parameters of bumetanide were infusion time‐dependent and it might be due to the saturable metabolism of bumetanide. For example, the mean values of CL (13.6, 25.3 vs 18.2 ml min−1 kg−1), MRT (9.70, 10.6 vs 21.8 min), Vss (128, 217 vs 378 ml kg−1), and CLNR (2.71, 9.24 vs 6.44 ml min−1 kg−1) increased when the same dose of bumetanide was infused in 1 h or 4 h. However, the mean values of t1/2, and CLR were not significantly different among three treatments. The diuretic effects (urine outputs and urinary excretions of sodium and chloride) increased significantly in 1 and 4 h of infusion although the total amounts of urinary excretion of unchanged bumetanide were 21.8 and 20.5 per cent lower in treatments II and III, respectively, when compared with the value in treatment I; the mean values of 8‐h urine outputs were 373, 922, and 1030 ml for 10s, 1 h, and 4 h of infusion, respectively, and the corresponding values for 24‐h sodium excretions were 49.0, 82.8, and 121 mmol, and for chloride were 47.5, 71.1, and 114 mmol. It could be due to the higher diuretic efficiencies in treatments II and III. Plasma concentrations of bumetanide, and hourly urine outputs and hourly urinary excretion rates of bumetanide, sodium, potassium, and chloride during the apparent steady state (between 1 and 4 h) in the 4 h infusion study were fairly constant.
Bioavailability of metformin in tablet form using a new high pressure liquid chromatography assay method
Authors: Caillé Gilles , Lacasse Yves , Raymond Manon , Landriault Hélène , Perrotta Maria , Picirilli Gianfranca , Thiffault Jean , Spénard Jean 
Published: October 2006

AbstractTwenty‐four young healthy volunteers received a single dose of metformin 500 mg (Glucophage®, Nordic Laboratories, Canada) in tablet form. Plasma concentrations were determined by HPLC in samples collected prior to and 0.33, 0.66, 1.33, 1.66, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 15, 18, 24, and 30 h after dosing. Mean (± SD) Cmax was 682.1 (160.6) ng ml−1 at a mean (± SD) tmax of 2.4 (0.93) h. Overall elimination was monoexponential with a mean (± SD) half‐life of 3.16 (0.47) h. We conclude that metformin is rapidly absorbed from this formulation and is also rapidly eliminated. Extrapolation to steady state predicts that equilibrium will be reached within 24 h.
Kinetic modeling of liposome degradation in blood circulation
Authors: Harashima Hideyoshi , Kume Yoshihiro , Yamane Chizu , Kiwada Hiroshi 
Published: October 2006

AbstractThe aim of this study is to develop a kinetic model for the quantitative evaluation of, and to examine dose dependency in liposome degradation in blood circulation in vivo. Multilamellar liposomes labeled with 3H‐inulin were administered intravenously into rats and the time courses of blood concentration and urinary excretion of 3H‐inulin were measured. The dosages of liposomes were fixed at 1, 5, and 100 μmolPCkg−1. Remarkable saturation was found in the time courses of both blood concentration and urinary excretion. Then a kinetic model for the degradation of liposomes in blood was developed, assuming that the degradation follows the first order rate process for each dose. The model fitted the observed time courses of excreted 3H‐inulin well, and dose dependency could be observed in the rate constants for liposome degradation, which are more sensitive than urinary excretion of 3H‐inulin. The degradation rate constant correlated well with the uptake rate constant, which suggests the same underlying mechanism for both uptake and degradation. These results indicate the usefulness of kinetic modeling in the quantitative evaluation of liposome degradation in blood circulation in vivo.
Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1‐methyl‐1‐cyclohexanecarboxylic acid
Authors: Liu Mei‐Jen , Pollack Gary M. 
Published: October 2006

AbstractThe pharmacokinetics of valproic acid (VPA) and three structural analogs, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1‐methyl‐1‐cyclohexanecarboxylic acid (MCCA), were examined in female Sprague‐Dawley rats. All four carboxylic acids evidenced dose‐dependent disposition. A dose‐related decrease in total body clearance was observed for each test compound, suggesting the presence of saturable elimination processes. Furthermore, the apparent volume of distribution for these compounds was, with the exception of CCA, dose‐dependent, indicating that binding to proteins in serum and/or tissues may be saturable. Both VPA and MCCA exhibited enterohepatic recirculation, although the degree of recirculation appeared to be dose‐ and compound‐dependent. Significant quantities of both VPA and MCCA were excreted in the urine as base‐labile conjugates, presumably representing glucuronides. In contrast, OA and CCA were not excreted in the urine as base‐labile conjugates and did not evidence enterohepatic recirculation. CCA displayed apparent Michaelis‐Menten kinetics, although the calculated Km was dose‐dependent. The results suggest that relatively minor changes in chemical structure have a marked influence on the metabolism and disposition of low molecular weight carboxylic acids.
Bioequivalence study of nalidixic acid tablets: In vitro–in vivo correlation
Authors: Jung H. , Gonzalez H. , Rodriguez J. M. 
Published: October 2006

AbstractThe USP dissolution test was used to select seven products with a wide range of dissolution characteristics for in vivo examination. The bioequivalence of seven (500 mg) products was evaluated in two crossover urinary excretion experiments. In each study three products were compared with the innovator product (Negram‐Winthrop‐Breon) in 12 subjects according to a 4 × 4 latin square design. Significantly different, lower bioavailability was observed in two products in relation to that of the innovator product. Linear in vitro–in vivo correlations were found between the cumulative amount excreted at 24 h and the log of the amount dissolved at 30 min and between log of the cumulative amount excreted up to 24 h and the log of the amount dissolved at 45 min.
Effect of infusion duration on valproate pharmacokinetics
Authors: Hussein Ziad , Patterson Karen J. , Lamm Janet E. , Cavanaugh John H. , Granneman G. Richard 
Published: October 2006

AbstractThe pharmacokinetics of intravenously administered valproic acid (VPA) were investigated in 16 healthy male volunteers in a single‐dose, fasting, four‐period, randomized, double‐blind, placebo‐controlled, parallel design study. Subjects were randomly assigned to be infused a single dose of sodium valproate equivalent to 1000 mg VPA or placebo over each of four different time periods. Valproate concentrations in plasma were determined using gas chromatography with flame ionization detection. The pharmacokinetic parameters were determined by both non‐compartmental and model‐dependent techniques. Analyses of variance (ANOVAs) were performed to detect any statistical differences among the regimens. Overall, the pharmacokinetics of valproate were similar after infusions of 5, 10, 30, and 60 min, with an average terminal‐phase half‐life of 15.9 h. There were modest differences in overall clearances among the regimens, with the 5 min infusion producing a mean area under the plasma concentration‐time curve (AUC; 1877 μg·h ml−1) that was significantly (13 to 16 per cent) higher than the means for the longer infusions (1614–1656 μg·h ml−1). Differences in distribution were also noted as a function of infusion duration. The shortest duration produced a significantly smaller terminal volume of distribution (12.8 vs 14.2–15.1 l) and more rapid tissue equilibration. The α‐phase rate constant declined from a mean of 5.1 h−1 after the 5 min infusion to a mean of 0.9 h−1 after the 60 min infusion. The distributional differences are almost certainly related to the saturable protein binding of valproate. However, the lower clearance after the 5 min infusion indicates that there may have also been partial saturation of one of the metabolic pathways of valproate during the distributive phase, and that the increase in fu was smaller than the decrease in CL′int, such that the product of fu·CL′int showed a net decrease.
Relationship between lung tissue and blood plasma concentrations of inhaled budesonide
Authors: Van Den Bosch J. M. M. , Westermann C. J. J. , Aumann J. , Edsbácker S. , Tönnesson M. , Selroos O. 
Published: October 2006

AbstractIn 11 patients, in whom a lung lobe or whole lung was to be resected, a single dose of 1.6 mg inhaled budesonide was given pre‐operatively. In 9 of them, concentrations of the drug in both lung tissue and blood plasma were measured. Budesonide concentrations in lung tissue, at least 90 min after dosage, were 2.1–8.9 nmol kg−1. Concentrations in blood plasma (0.27–1.1 nmol kg−1) were 1/8th of those in lung tissue.
Effects of water deprivation on the pharmacokinetics and pharmacodynamics of bumetanide in rats
Authors: Huang Ji Y. , Kim Ok N. , Lee Sun H. , Lee Myung G. 
Published: October 2006

AbstractThe effects of temporary water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of bumetanide were examined after intravenous (i.v.) administration of bumetanide, 8 mg kg−1 to control and water deprived rats (n = 7). The values of AUC, t1/2 and MRT increased 79.0, 417, and 633 per cent, respectively, and CL and CLNR decreased 44.0 and 41.2 per cent, respectively, in water deprived rats. They were all significantly different. The decreased CLNR in water deprived rats could be due to decreased nonrenal metabolism of bumetanide; it could be supported that the amounts of glucuronide conjugate of bumetanide (52.5 vs 12.9 μg), desbutylbumetanide (170 vs 113 μg) and its glucuronide conjugation (191 vs 125 μg), and sum of the three metabolites (414 vs 229 μg), which are expressed in terms of bumetanide excreted in 24 h urine, decreased significantly in water deprived rats. The 8‐h urine outputs per 100 g body weight (4.32 vs 1.34 ml) also reduced significantly in water deprived rats, and it might be due to significantly reduced amounts of bumetanide excreted in 8 h urine (90.9 vs 25.7 μg) and/or reduced kidney function in water deprived rats. The kidney function based on CLlot (9.87 vs 2.14 ml min−1 kg−1) reduced significantly in water deprived rats. The 8‐h urinary excretions of sodium (0.430 vs 0.0818 mmol), potassium (0.567 vs 0.270 mmol), and chloride (0.549 vs 0.0624 mmol) per 100 g body weight also reduced significantly in water deprived rats.
Disposition of enantiomers of sulpiride in humans and rats
Authors: Kamizono Ayako , Inotsume Nobuo , Fukushima Shoji , Nakano Masahiro , Okamoto Yoshio 
Published: October 2006

AbstractPharmacokinetics of sulpiride enantiomers after intravenous administration of (±)‐, (+)‐, and (−)‐sulpiride was examined in humans and rats. Pharmacokinetic profiles were similar in (+)‐ and (−)‐enantiomers after intravenous administration of (±)‐sulpiride. Metabolic inversion at a chiral centre was not observed after intravenous administration of each enantiomer in rats.
Relationship between content of hepatic glutathione S‐transferases and the kinetics of indocyanine green elimination in various liver diseases
Authors: Sugimoto Motonobu , Shimada Nagaki , Aikawa Katsunori , Sugiyama Yuichi 
Published: October 2006

AbstractThe glutathione (GSH) S‐transferases are believed to have dual functions as hepatic detoxifying enzymes and intrahepatic binding proteins. Little is known about their alterations in human liver diseases. Therefore, we have studied the relationship between the enzyme activity and rose bengal (RB) binding in hepatic cytosol and plasma indocyanine green (ICG) kinetics in patients with various liver diseases. The enzyme activity was measured in samples of hepatic cytosol obtained from 52 patients. In addition, the content of cationic and neutral transferases was estimated in 17 biopsy samples by densitometry of Coomassie blue stained sodium dodecyl sulphate polyacrylamide gel electrophoretograms. RB binding studies also were performed on cytosol samples. ICG kinetic parameters were determined using the two‐compartment open model in 17 patients who were given the dye (0.5 mg kg−1) intravenously. Correlations between the enzyme activity and liver function tests, content of the enzyme, RB binding and ICG kinetic parameters were evaluated. The following results were obtained. (1) The enzyme activities were high in alcoholic liver disease, fatty liver and Gilbert's syndrome, and low in cirrhosis. (2) The enzyme activities were positively correlated with serum cholinesterase activity, serum albumin level and hepaplastin test, and negatively correlated with ICG retention rate at 15 min. (3) The enzyme activity, its content and RB binding affinity of the cytosol were positively correlated with each other. (4) The enzyme activity was positively correlated with hepatic ICG distribution volume. These results are consistent with the role of the GSH S‐transferases as ligandins in intracellular storage of dyes.
Pharmacokinetic profiles of glycyrrhizin in patients with chronic hepatitis
Authors: Tanaka Naomi , Yamamura Yoshikazu , Santa Tomofumi , Kotaki Hajime , Uchino Katsuyoshi , Sawada Yasufumi , Aikawa Tatsuya , Osuga Toshiaki , Iga Tatsuji 
Published: October 2006

AbstractThe pharmacokinetics of glycyrrhizin (G) in eight patients with chronic hepatitis receiving chronically i.v. administration of 120 mg dose of G was investigated. The plasma concentration of G in the patients after dosing declined in a monophasic manner. However, the pharmacokinetic profiles varied among patients. The mean elimination half‐life (t1/2) and the total body clearance (CLtot) were 6.0 h (range 4.3–10.7 h) and 7.9 ml h−1 kg−1 (4.5–12.7 ml h−1 kg−1), respectively. The variation of the CLtot for G was closely related to that of aspartate aminotransferase (r = −0.739, p <0.05) and alanine aminotransferase (r = −0.783, p <0.05) activities in the plasma.
Cyclosporin A and erythromycin: A study of a drug interaction in the in situ perfused rat liver model
Authors: Hughes C. M. , Swanton J. G. , Collier P. S. 
Published: October 2006

AbstractUsing the in situ perfused rat liver model, the effect of erythromycin (Ery) on the disposition of cyclosporin A (CyA) and the major human metabolite, AMl, was investigated. Prior to perfusion experiments, oral dosing was carried out for three days on three groups of male Sprague—Dawley rats (300–350 g), involving pretreatment with water (control and H2O/Ery groups) or erythromycin (Ery oral group). On the fourth day, perfusion experiments took place using standard techniques, with the addition of 20 mg Ery to the H2O/Ery and Ery oral groups, and 2.5 mg CyA to all groups. Perfusate and bile samples were collected and assayed for CyA and AMl by HPLC. Results indicated that inhibition of CyA metabolism had occurred as the CyA concentration in perfusate was significantly higher in both Ery groups at all times compared to the control group, and the levels of AMl in both perfusate and bile were significantly lower than in the control group. There was also a marked reduction in the apparent metabolic clearance of CyA in the Ery groups. It was concluded that AMl production had been inhibited by Ery, the most likely mechanism being inhibition of the isoenzyme CYP3A with which Ery forms a stable complex.