bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of pregnancy on the biotransformation and urinary excretion of methoxyphenamine in mice
Authors: Foster Brian C. , Wilson D. Lynden , Cyr Terry D. , Moffatt James , Buttar Harpal S. 
Published: October 2006

AbstractThe urinary elimination of methoxyphenamine (MPA) and its metabolites in underivatized samples was examined after single and multiple oral administration to pregnant and non‐pregnant mice by GLC and GLC—MS.The major metaboliteO‐desmethylmethoxyphenamine (ODMP), along with lesser amounts ofN‐desmethylmethoxyphenamine (NDMP) and 2‐hydroxyamphetamine (2OH), were the only metabolites detected in urine extracts of pregnant and non‐pregnant mice. 5‐Hydroxymethoxyphenamine (5HMP) was not detected. Enzyme hydrolysis did not increase the recovery of either substrate or metabolites in either the pregnant or non‐pregnant animals. The results show that MPA metabolism in the Swiss—Webster mouse is distinctly different from that seen in man and other laboratory animals.The mean MPA:ODMP ratio in day‐6 urine from pregnant mice after a single dose was 0.31 ± 0.04. The NDMP:ODMP ratios were less than 0.10 in all samples. Non‐pregnant mice urine had equivalent amounts of MPA, NDMP, ODMP, and 2OH after multiple dosing.While multiple dosing and pregnancy did not alter either the urinary recovery or profile of the metabolites detected, there was a linear decrease in the MPA:ODMP ratio during gestation.MPA was extensively metabolized to ODMP in the male mice, and the MPA:ODMP ratio of 0.41 was slightly higher than that observed in the pregnant and non‐pregnant females.
An in vitro study of the influence of a drug's molecular weight on its overall (Clt), diffusive (Cld) and convective (Clc) clearance through dialysers
Authors: Mac‐Kay M. Valera , Fernandez I. Perez , Carranza J. Herrera , Burson J. Sanchez 
Published: October 2006

AbstractThe dialyser clearance of a drug is the sum of two components: one diffusive, arising from the concentration gradient across the membrane, and the other convective, arising from the ultrafiltration of plasma water, produced by the increases in hydraulic pressure that the membrane undergoes.To demonstrate the importance of these clearnces during haemodialysis, this study analyses the influence of a drug's molecular weight on them.To this end, an experimental study of dialysis in vitro was carried out to determine the clearances, in aqueous solution, of five drugs of increasing molecular weights (theophylline, quinidine, tobramycin, digoxin, and vancomycin), using two series of dialysers with the same type of membrane (Cuprophan®), differing in effective surface area and ultrafiltration coefficient.From the data obtained in this study, the importance of quantifying convective clearance during haemodialysis becomes apparent since if it is not taken into account errors of up to 20% and more may be made. This is particularly so if the drug is of high molecular weight and if a high filtration rate is being used.
An evaluation of numerical integration algorithms for the estimation of the area under the curve (AUC) in pharmacokinetic studies
Authors: Yu Zhiling , Tse Francis L. S. 
Published: October 2006

AbstractSix numerical integration algorithms based on linear and log trapezoidal methods as well as four cubic‐spline methods were proposed for estimation of area under the curve (AUC). These six different algorithms were implemented using IMSL/IDLTM command language and evaluated using data simulated under five different dosing conditions and two different sampling conditions. Comparisons between AUC estimations using these six different algorithms and the theoretical results were made in terms of both overall AUC values and the superimposability of the concentration‐time profiles. In well designed studies with ample data points, the algorithm based on IMSL/IDLTM function CSSHAPE with concavity preservation gave the best performance. In contrast, when the frequency of blood collection was limited, the algorithm based on the log trapezoidal rule proved to be stable with reasonable accuracy, and is recommended as the practical method for numerical interpolation and integration in pharmacokinetic studies. Algorithms based on the combination of the log trapezoidal rule and cubic‐spline methods using IMSL/IDLTM function CSSHAPE can be developed to enhance overall performance.
Pharmacokinetics of the novel anticonvulsant hepp after single intravenous administration of three different doses in dogs
Authors: Gómez M. Lisbeth E. , Lehmann F. Pedro A. 
Published: October 2006

AbstractHEPP (D, L‐3‐hydroxy‐3‐ethyl‐3‐phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low toxicity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg−1. A biphasic disappearance pattern with a rapid distribution phase was observed in the plasma concentration versus time curve. The mean terminal half‐life (t1/2β) was the same after the three doses (3.4±0.15h) and the mean half‐lives of the distribution phase (t1/2α) were not significantly different after the three doses (0.09±0.02, 0.08±0.07, and 0.11±0.03 h for 8, 15, and 30 mg kg−1 respectively). The mean AUC0‐∞ values were 44.1±10.8, 72.1±8.8, and 127.4±23.2 μg h mL−1, respectively, showing a linear increase. The individual values of AUC0‐∞ corrected for the administered dose (AUC0‐∞/D) were 0.29±0.04, 0.23±0.05, and 0.22±0.06 h mL−1. These values were not statistically different. Neither the mean residence time (MRT=4.55±1.50, 4.90±1.32, and 5.07±1.95 h), the steady state volume of distribution (Vss=0.86±0.11, 1.01±0.17, and 1.20±0.40 L kg−1) nor the systemic clearance (Cl=3.36±0.82, 3.53±0.44, and 4.02±0.68 mL min−1 kg−1) showed significant differences between doses. The values of Vss suggest that HEPP is distributed in the whole body fluid. The invariant pharmacokinetic parameters and the direct correlation between AUC0‐∞ and the dose suggest that the kinetics of HEPP in dogs are linear over the range of doses studied.
Kinetic modelling of liposome degradation in peritoneal macrophages
Authors: Harashima Hideyoshi , Hirai Noriko , Kiwada Hiroshi 
Published: October 2006

AbstractThe objective of this study was to quantify and model the degradation process of liposomes in peritoneal macrophages (PMs). Iodinated albumin (125I‐alb) was chosen to be the marker of liposome degradation. The time course of the degradation of free 125I‐alb after pinocytosis by PMs followed first‐order kinetics with a half‐life of 23 min. The degradation of liposomally encapsulated 125I‐alb was also quantified. Kinetic modelling of liposome degradation indicated the existence of two kinetically different processes, one with a half‐life of 13 min and the other with a half‐life of 7.5 h. Comparing the degradation of liposomal and free 125I‐alb suggested that 125I‐alb was delivered to lysosomes much faster through phagocytosis than pinocytosis. These results indicate that the intracellular degradation kinetics of pinosomes and phagosomes is different. This method can quantify the rate and extent of liposomal degradation in macrophages and provide kinetic information on the intracellular destiny of liposomally encapsulated compounds.
Dose proportionality of stavudine in hiv seropositive asymptomatic subjects: Application to bioequivalence assessment of various capsule formulations
Authors: Kaul Sanjeev , Mummaneni Vanaja , Barbhaiya Rashmi H. 
Published: October 2006

AbstractThe dose proportionality and bioequivalence of the capsule formulations used in clinical trials and the proposed commercial formulations of stavudine were assessed in an openlabel, single‐dose, randomized four‐way crossover study in 16 asymptomatic HIV‐infected males. One capsule of stavudine (5, 10, 20, or 40 mg) was administered orally to each subject in each of the four treatment periods. Serial blood samples were collected for 10 h after each dose and the plasma was assayed for intact stavudine by a validated radioimmunoassay method. The plasma concentration‐time data were subjected to noncompartmental pharmacokinetic analysis. For doses ranging from 5 to 40 mg, meanCmaxand AUC0‐∞values were in the range of 110.36–889.34 ng mL−1and 246.46–1945.97 h ng mL−1respectively. The meanCmaxand AUC0‐∞of stavudine increased in a dose‐proportional manner. Irrespective of the dose, meanCmaxvalues were observed at a mediantmaxof 0.75 h or less. Meant1/2values were 1.97, 1.77, 1.67 and 1.66 h for the 5, 10, 20, and 40 mg capsules, respectively. For bioequivalence assessment,Cmaxand AUC0‐∞values were normalized to the 10 mg dose since these parameters were dose proportional. The 10 mg capsule formulation used in phase‐3 clinical trials was chosen as the reference. The relative bioavailability estimates and 90% confidence limits for the dose‐normalizedCmaxvalues with the 10 mg capsule as the reference were 86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20, and 40 mg capsules, respectively. The differences in the point estimates of the dose‐normalized AUC0‐∞values for the 5, 20, and 40 mg capsules relative to the 10 mg phase‐3 capsule were 1% or less, and the 90% confidence limits were all within 95–106%. These results indicate that stavudine exhibits linear pharmacokinetics and that the 5, 10, 20, and 40 mg capsules of stavudine are bioequivalent.
Pharmacokinetics of dolasetron following single‐ and multiple‐dose intravenous administration to normal male subjects
Authors: Shah Ajit , Lanman Robert , Bhargava Vijay , Weir Scott , Hahne William 
Published: October 2006

AbstractDolasetron, AnzemetTM, a 5‐hydroxytryptamine receptor antagonist, is under investigation as an antiemetic agent. The keto‐reduced metabolite of dolasetron has been identified in human plasma and is probably responsible for the majority of the antiemetic activity. This study evaluated the pharmacokinetics of dolasetron and the reduced metabolite following single and multiple intravenous (IV) infusions of dolasetron mesylate in healthy male subjects. Four groups of subjects (six active/two placebo) received either dolasetron mesylate or placebo in single IV doses ranging from 0.30 to 0.60 mg kg−1 on day 1 and multiple IV doses ranging from 0.60 to 1.20 mg kg−1 d−1 on days 2–9. Dolasetron could be detected for less than 1 h, while the reduced metabolite appeared rapidly in the plasma, reaching a maximal plasma concentration in less than 1 h. Reduced metabolite maximal plasma concentration was proportional to the dose and the area under plasma concentration curve was linear based on regression analysis. The half‐life of reduced metabolite ranged from 3.82 to 7.46 h. The mean renal clearance of reduced metabolite was 2.20–4.43 mL min−1 kg−1 and was dose independent. All of the evidence supports dose independent pharmacokinetics for the reduced metabolite. Upon multiple dosing, the reduced metabolite AUC can be predicted from the single‐dose pharmacokinetics of this metabolite.
The influence of food intake on the effect of two controlled release formulations of furosemide
Authors: Paintaud G. , Alván G. , Eckernäs S.‐Å. , Wakelkamp M. 
Published: October 2006

AbstractDifferences in the urinary excretion rate of furosemide may explain discrepancies observed between the bioavailability and the total diuretic effect of different formulations of this drug. Furosemide was given at a dose of 60 mg as two oral controlled release (CR) formulations (FR and LR), with and without breakfast, in a randomized, four‐treatment, four‐period, crossover design to 28 healthy volunteers. Urinary volume, and contents of furosemide and sodium, were measured in samples taken over 24 h. The extent and rate of absorption of furosemide from FR were decreased after breakfast as compared to fasting: the mean (SD) of total furosemide excreted decreased from 11.38 (3.12) to 7.73 (1.67) mg, p<0.0001, and the median (range) mean residence time increased from 6.3 (4.1–9.3) to 9.5 (5.9–11.8) h, p <0.001. On the other hand, the extent of absorption of LR was increased after breakfast, from 8.04 (3.32) to 9.45 (1.83) mg, p <0.05, without a significant change in MRT. FR had a higher extent and rate of absorption than LR during fasting, but its extent of absorption was lower than that of LR in the postprandial state. Interestingly, the total fraction of furosemide absorbed, as estimated from total furosemide excretion, was not correlated with the total diuresis (r2 = 0.079) and the differences in drug response compared among the four periods were much smaller than would be expected from the differences in amount absorbed. This discrepancy may be explained by differences in urinary excretion rate of furosemide and, related to this, differences in efficiency profiles between the four treatments. Therefore, the urinary excretion profile of a formulation of furosemide may be more important for the cumulated drug effect than the amount absorbed.
The influence of pyruvic acid on the pharmacokinetics of sulphadiazine in rabbits
Authors: Hsu Kuang‐Yang , Song Dah‐Jing , Ho Yih 
Published: October 2006

AbstractDuring the past few years, acetylation polymorphism has been shown to be a proven, established fact, and N‐acetyltransferase, an enzyme that transfers an acetyl group to the substrate, has been recognized as the main factor in acetylation polymorphism. In a recent study, a significant difference between the acetylation phenotype and plasma pyruvic acid (PA) concentration in rabbits was found. In this report, the influence of PA on the pharmacokinetics of sulphadiazine (SDZ), a drug that has been used in pharmacogenetic studies of acetylation, was studied. By using a loading dose of 300 mg kg−1, and an infusion rate of 7.5 mg min−1 of kg−1 of PA, the concentration of PA reached a steady state (Css∽100 μg mL−1) in 30 min. During PA infusion in rapid‐acetylation rabbits, no significant changes were found in any of the pharmacokinetic parameters for SDZ. However, differences were found in the β half‐life, AUC, clearance, and k10 of SDZ in slow acetylators: the β half‐life decreased from 115.74 ± 12.47 min to 62.96 ± 4.36 min (p < 0.001); AUC decreased from 10 617.38 ± 1179.81 μg mL−1 to 6217.14 ± 391.32 μg min mL−1 (p < 0.001); clearance increased from 0.0044 ± 0.0008 L min−1 kg−1to 0.0068 ± 0.0007 L min−1 kg−1 (p < 0.001); and k10 increased from 0.0090 ± 0.0009 min−1 to 0.0193 ± 0.0028 min−1 (p < 0.005). The reason for this may be that PA influences the elimination of SDZ in slow‐acetylation rabbits.
Absorption of new HIV‐1 protease inhibitor, KNI‐272, after intraduodenal and intragastric administrations to rats: Effect of solvent
Authors: Sugahara M. , Kiriyama A. , Hamada Y. , Kiso Y. , Takada K. 
Published: October 2006

AbstractKNI‐272 is a tripeptide drug that has a strong pharmacological potential for treating human immunodeficiency virus type 1 (HIV‐1). We have already reported the pharmacokinetic characteristics of KNI‐272 after intravenous and intraduodenal (ID) administrations to rats. In this study, KNI‐272 was administered to rats as a solution and the effect of four kinds of solvent on the bioavailability (BA) of KNI‐272 was determined using rats. The mixtures included propylene glycol (PG) and water (70% PG), a solution of PG (100% PG), a solution of Tween 80 (Tween 80), and a mixture of PG and HCO60, a polyoxyethylated, 60μmol, castor oil derivative (PG:HCO60=7:3). After ID administration to rats at a dose of 50.0 mg kg−1, the mean peak plasma concentrations, Cmax, were 2.58±0.53 (SE) (70% PG), 3.28±0.51 (100% PG), 3.15±0.51 (Tween 80), and 4.66±0.68 μg mL−1 (PG:HCO60). The highest BA, 44.6%, was obtained after ID administration of KNI‐272 dissolved in PG:HCO60. On the other hand, after intragastric (IG) administration of KNI‐272 solution in which the drug was dissolved with PG:HCO60, the Tmax, the Cmax, and the BA were 1.25±0.60h, 2.33±0.65 μg mL−1, and 24.2%, respectively. The Cmax and BA values were equal to half of the values obtained after ID administration of KNI‐272 dissolved in the same solution. In this study, as the PG concentration in the solution increased and the other additives (Tween 80 and HCO60) were coadministered, the BA of KNI‐272 after ID administration increased. These results suggest that, for the development of an oral dosage form of KNI‐272, a non‐ionic surfactant that dissolves in the duodenum or small intestine and that enhances the absorption of this drug from the gastrointestinal tract into the enterocytes is needed.
Pharmacokinetics of methotrexate after intravenous and intramuscular injection of methotrexate‐bearing positively charged liposomes to rats
Authors: Kim Myoung M. , Lee Sun H. , Lee Myung G. , Hwang Sung J. , Kim Chong‐K. 
Published: October 2006

AbstractThe pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (IV) and intramuscular (IM) injection of free MTX (treatment I), freshly prepared MTX‐bearing positively charged liposomes (large unilamellar vesicles), PLUVs (treatment II), and empty PLUVs mixed manually with free MTX (treatment III), 4 mg kg−1 as free MTX to rats, using HPLC assay. After 1 min IV infusion, the plasma concentrations of MTX (Cp), the area under the plasma concentration—time curve (AUC, 173 against 314 μg mL min−1), the terminal half‐life (t1/2, 24.0 against 412 min), the mean residence time (MRT, 13.0 against 324 min), and the apparent volume of distribution at steady state (VSS, 289 against 3370 mL kg−1) were significantly larger, but the total body clearance (CL, 23.1 against 12.8 mL min−1 kg−1), the renal clearance (CLR, 8.38 against 3.09 mL min−1 kg−1), the non‐renal clearance (CLNR, 14.6 against 9.56 mL min−1 kg−1), and the amount of MTX excreted in urine (Xu, 415 against 275 μg) were significantly lower in treatment II than in treatment I. This could be due to the fact that some of the MTX‐bearing PLUVs were entrapped in tissues and the rest were present in plasma (larger MRT and Vss in treatment II), and MTX is slowly released from MTX‐bearing PLUVs (longer t1/2 in treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX in MTX‐bearing PLUVs (larger Cp and AUC and slower CL in treatment II). Saturable formation of 7‐hydroxymethotrexate from MTX was reported in rabbit blood and non‐linear disposition of MTX was also reported in rats and rabbits (lower Xu and CLR in treatment II). After 1 min IV infusion, some pharmacokinetic parameters of MTX, such as AUC, CL, CLR, CLNR, and Xu, were significantly different between treatments I and III, but nonetheless the differences were smaller than those between treatments I and II. After both IV and IM administration, the amount of MTX remaining per gram of tissue or organ in the kidney, stomach, small intestine, and large intestine was significantly smaller in treatment II than in treatment I. Such tissue results imply that the side‐effects of MTX on kidney and GI tract could be reduced after both IV and IM administration of MTX‐bearing PLUVs rather than free MTX. The encapsulation efficiency of MTX in MTX‐bearing PLUVs was 5.47%, and MTX was released slowly from MTX‐bearing PLUVs when incubated in phsophate buffered saline, rat plasma and rat liver homogenates.
Time course of cyclosporine and its metabolites in blood, liver and spleen of naive lewis rats: Comparison with preliminary data obtained in transplanted animals
Authors: Wacher Vincent J. , Liu Tao , Roberts John P. , Ascher Nancy L. , Benet Leslie Z. 
Published: October 2006

AbstractThe time course of intravenously administered cyclosporine (1mg kg−1) and its metabolites AM1, AM9, and AM1c were examined in the blood, liver, and spleen of naive Lewis rats. Cyclosporine concentration versus time data for all three tissues were qualitatively similar, following a biexponential modelC=Ae+Bewith maximum cylosporine concentrations reached at 1h. Whole‐blood cyclosporine clearance, terminal half‐life, mean residence time, steady state volume of distribution, and hepatic extraction ratio (calculated from blood data) were similar to previously reported results. Cyclosporine in the liver showed the largest area under the concentration—time curve, mean residence time, and disposition and terminal half‐lives. Spleen cyclosporine mean residence time and terminal half‐life were not significantly different from blood parameters. Metabolites AM1, AM9, and AM1c showed almost parallel time courses in all three tissues. The hydroxylated derivative AM9 was the major metabolite found in all tissues, with twofold greater levels in the liver compared to the blood and the spleen. Slightly less AM1 was found in the liver relative to blood and spleen, where it was present in equal amounts. AM1c levels in the liver were not different from those in the spleen and were greater than observed for blood. The results obtained above were reflected in preliminary studies using liver transplanted rats treated with multiple doses of cyclosporine. Both blood and liver biopsy levels of CyA, AM1, and AM9 post‐transplant showed twofold to fourfold decreases from day 3 (samples taken 4h post‐CyA‐dose) to day 7 (samples taken 24h post‐CyA‐dose) and concentrations were not significantly different from similarly sampled naive controls. More importantly, the metabolite/CyA ratios did not vary significantly between liver and blood in the two groups. For naive rats, and liver transplanted animals not undergoing rejection, changes in blood cyclosporine levels seem to predict variations in tissue concentrations.
Methodology for using oral dose pharmacokinetic data to select drugs for prolonged release formulations and validation of the method using simulated data
Authors: Zhou Mingxing , Notari Robert E. 
Published: October 2006

AbstractA computer aided method for selecting drugs as potential candidates for oral prolonged release formulations has been previously published. In order to decide whether trial formulations were warranted, prolonged release dosing was simulated to find all release rates and doses producing successful regimens in every subject for whom clinical pharmacokinetic data were available. Intravenous dose data were required because the models and their parameter values could not be assessed with oral doses. The new method uses model independent equations derived from rapidly absorbed oral doses to simulate the administration of prolonged release formulations. Using these equations, repetitive oral dosing regimens were reiteratively simulated to search for all successful release rates and doses in every available subject. Results were validated by comparison to those obtained with the published method using theophylline and hypothetical drugs, which included examples of flip‐flop and vanishing exponentials. When the oral reference dose data were reliable, results were similar even when the model independent parameter values did not agree with those used to generate the oral reference dose data. Differences were observed only when the random errors in the oral reference dose data were large. If more than one model independent equation provided equivalent fits to the oral reference dose data, the final results were similar independent of which equation was employed.