bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioavailability of chlorothiazide from 50, 100, and 250 mg solution doses
Authors: Osman M. A. , Patel R. B. , Irwin D. S. , Craig W. A. , Welling P. G. 
Published: October 2006

AbstractThe bioavailability of chlorothiazide was examined following single oral solution doses to eight healthy male volunteers. Drug was administered in 250ml of water after overnight fast. Bioavailability was determined by measuring 72 h urinary recovery of unchanged drug. Mean urinary recovery from 50, 100, and 250 mg doses was, respectively, 28.3, 47.0, and 83.3 mg, representing 56.4, 47.0, and 33.3 per cent of the administered dose. The correlation coefficient between dose size and percentage recovery was −0.662. These results add support to previous suggestions that the absorption of chlorothiazide from the gastrointestinal tract is saturable, and that the bioavailability of chlorothiazide may be similar to that of hydrochlorothiazide when these compounds are administered in the same dosage range.
Salicylamide pharmacokinetics in healthy males: Dietary effect
Authors: Morad Abdel‐Rehim M. 
Published: October 2006

AbstractThe effect of diet on the absorption, metabolism, and elimination of salicylamide (SAM) in man was studied in five healthy male volunteers. In a three‐way cross‐over study, 300 mg SAM capsules were administered under fasting, carbohydrate, and lipid diet conditions. Total urinary salicylates, salicylamide glucuronide (SAMG), and salicylamide sulphate (SAMS) were determined at different time intervals. Diet was found to have no significant effect on the extent of SAM absorption or on its apparent elimination half‐life. A significant increase (P< 0.001) in the fraction excreted as SAMS in the lipid diet trial compared to the fasting or carbohydrate trials is observed. In the lipid diet trial, the ratio (R) of the cumulative urinary SAMS/SAMG was found to be 1.5–3 times the ratio obtained under fasting or carbohydrate diet conditions. The equilibrium solubilities of SAM under physiologic conditions in water (W), simulated intestinal fluid (M), and corn oil (O) were 4.08, and 4.81, and 12.5mgml−1, respectively. The equilibrium apparent distribution coefficients KO/W'KO/W, and KM/W were 3.1, 2.6, and 1.18, respectively. The increase in R is probably due to a decrease in free SAM concentration at the absorption site (intestinal mucosa) in the presence of lipids. A model for drug distribution in the gastrointestinal tract during lipid digestion is proposed and discussed.
Buccal uptake, urinary excretion, and physicochemical properties of zipeprol and its N‐dealkylated products
Authors: Achari R. , Beckett A. H. 
Published: October 2006

AbstractBuccal uptake, partition characteristics, ionization constants, and urinary excretion were studied for zipeprol and two of its metabolities. Buccal uptake, measured in a single subject, was found to be correlated with n‐heptane/water (ph 7.4) partition values of the compounds, and with proportional excreation of the unchanged drug. The importance of the shape of buccal uptake‐pH curves in the prediction of absorption and excretion of these compounds is discussed.
Excretion of digoxin and its metabolites in urine after a single oral dose in healthy subjects
Authors: Magnusson J. O. , Bergdahl B. , Bogentoft C. , Jonsson U. E. , Tekenbergs L. 
Published: October 2006

AbstractThe 3‐day urinary excretion of digoxin, its conjugated and unconjugated hydrolytic metabolites and dihydrodigoxin, was studied in 8 healthy men after oral administration of tritiated digoxin. Analysis was performed by high pressure liquid chromatography (HPLC). The total radioactivity corresponded to 45.4±2.0 per cent (mean ± S.E.M.) of the dose. By HPLC 424 ± 2.7 per cent was recovered before and 44.0 ± 2.7 per cent after deconjugation of the samples. Digoxin and dihydrodigoxin constituted 40.3 ± 2.9 per cent; of this 0.7 ± 0.4 per cent was dihydrodigoxin. The sum of the hydrolytic metabolites was 2.1 ± 0.3 per cent before and 3.4± 0.5 per cent after deconjugation. No correlation was found between gastric pH and the production of hydrolytic metabolites. The relative amount of these metabolites was maximal (mean 13.4 per cent of the excretion) in the 4.8 h sampling period. During the first 8 h an average of 8.6 per cent of the radioactivity was not recovered by HPLC. The metabolism of digoxin as judged by urinary excretion was limited and showed great variation during the early hours after treatment. The excretion of unchanged digoxin in some individuals constituted as little as 60 per cent over the first 12 h after dosing.
Effect of sustained release on the pharmacokinetic profile of indomethacin in man
Authors: Yeh K. C. , Berger E. T. , Breault G. O. , Lei B. W. , McMahon F. G. 
Published: October 2006

AbstractThe effect of sustained release on the pharmacokinetic profile of indomethacin was examined by comparing to three reference regimens: an intravenous dose, a single 75 mg dose of conventional capsules, and three 25 mg conventional doses given at 4‐h intervals. Results indicate that the sustained release test formulation exhibited more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion, and showed an overall bioavailability of 0.93 (95 per cent C.I. = 0.82, 1.04) relative to three 25 mg doses of the conventional capsules.
The disposition of diphenhydramine and four of its analogues in rabbits and implication for structure‐activity relationship studies in drug design
Authors: Parry Rosalind , Calvert R. T. 
Published: October 2006

AbstractThe disposition of diphenhydramine (I) and four of its ring substituted analogues, 4‐bromodiphenhydramine (II), 4‐methyldiphenhydramine (III), 2‐methyldiphen‐hydramine (IV), and 4‐t‐butyldiphenhydramine (V), was investigated in the rabbit, during and after intravenous infusion.The concentration of each analogue was determined by gas‐liquid chromatography (GLC) and the disposition parameters of clearance, volume of distribution, and elimination rate constant determined. These parameters were found to vary within the series, clearance increased in the order I < IV < III < II < V and volume of distribution in the order III < I < IV < V < II. These changes correlated with the Hansch hydrophobic substituent parameter: for clearance r = 0.97, for volume r = 0.7.The implication of these changes for the design of studies investigating the effects of structure on pharmacological response are discussed.
Pharmacokinetics of 14C‐DMPS (sodium‐1,3 14C‐2,3‐dimercaptopropane‐l‐sulphonate) in beagle dogs
Authors: Wiedemann P. , Fichtl B. , Szinicz L. 
Published: October 2006

AbstractThe pharmacokinetics of labelled DMPS (sodium‐1,3 14C‐2,3‐dimercaptopropane‐1‐sulphonate) have been studied in four beagle dogs following bolus intravenous injection (65‐7 μmolkg−1) and oral administration (197μmol kg−1). Following intravenous injection the main kinetic parameters were t1/2 = 43min, Vβ = 160 ml kg−1, and plasma clearance Clp = 2.6ml min−1 kg−1.Following oral administration 14C‐DMPS is rapidly absorbed with peak concentrations (478 ± 25 umol 1−1) measured after 30–45 min. About 60 per cent of the oral dose was absorbed. Estimates of t1/2, Vβ, and Clp after oral administration were in close agreement with the values obtained in the intravenous study.14C‐DMPS is eliminated from the body by the kidneys. About 70 per cent of 14C‐DMPS in dog plasma are bound to proteins. Binding is even higher in plasma from rat and man.
Comparative bioavailability of S‐carboxymethylcysteine from two dosage forms: Hard gelatin capsule and syrup
Authors: Aiache J‐M. , Borel J. P. , Kantelip J‐P. 
Published: October 2006

AbstractMeasurement of plasma concentrations after the oral administration of S‐carboxymethylcysteine in two different dosage forms, as a hard gelatin capsule and as a syrup, shows its relative bioavailability from the two formulations to be similar. With the exception of the time required to reach peak concentration, which shows a slight variation attributable to the time taken for the drug to be released from the capsule and to dissolve, parameters such as peak concentration, biological half‐life and area under the serum‐concentration curve whether from t=0 to t = 8h or from t = 0 to t=∞, are not statistically different. The areas under the plasma‐concentration curves between t = 0 and t = 8 h and between t = 0 and t = ∞ shows that for a confidence limit of 95 per cent, the mean for the capsular form does not differ by more than 3.3–10.3 per cent from the mean for the syrup.
Esterase distribution in the rabbit cornea and its implications in ocular drug bioavailability
Authors: Lee Vincent H.‐L. , Morimoto Kim W. , Stratford Robert E. 
Published: October 2006

AbstractBeing the major pathway by which topically applied ophthalmic drugs enter the eye, the cornea can control the amount of active drug ultimately absorbed by offering resistance to drug permeation and by metabolizing the drug during permeation. This research seeks to determine the esterase activity in the cornea and two of its component layers— epithelium and stroma‐endothelium—so as to anticipate the extent to which drugs containing ester linkages will be metabolized during transport. This has been achieved by incubating corneal homogenates of albino and pigmented rabbits of various age groups with α‐naphthyl acetate, the model substrate, and monitoring the fluorescence intensity due to α‐naphthol as a function of time. The results indicate that: (1) esterase activity in the epithelium is approximately twice that in the stroma‐endothelium; (2) esterase activity in the intact cornea is linearly related to those in the epithelium and the stroma‐endothelium; and (3) the esterase activity in the cornea and its component layers varies with rabbit's age and strain. According to these results the bulk of esterase‐mediated hydrolysis is expected to take place in the epithelium, so that the residence time of a drug in this tissue can have a significant impact on its ocular bioavailability.
Bioavailability of a commercial sustained‐release quinidine tablet compared to oral quinidine solution
Authors: Sawyer William T. , Pulliam Charles C. , Mattocks Albert , Foster James , Hadzija B. Wesley , Rosenthal Harold M. 
Published: October 2006

AbstractThe bioavailability of quinidine sulfate after oral administration of a commercial sustained‐release quinidine tablet was compared with that of oral quinidine sulfate solution in 18 normal subjects. Three hundred milligrammes of each product was administered to each subject in standard cross‐over fashion on separate occasions, with plasma quinidine levels measured for 46 h after each dose. Although peak plasma quinidine levels were lower, and occurred later, after tablet administration than after solution, analysis of the area under the plasma quinidine level‐time curve (AUC) values for each product indicated that the products were equivalent, in terms of the extent of absorption, with the mean AUC (0–46h) value for the tablet, 8744.4 ng × h ml−1, comparable to that of the solution, 9145.9 ng × h ml−1.
Bioavailability of bromhexine tablets and preliminary pharmacokinetics in humans
Authors: Bechgaard E. , Nielsen Anni 
Published: October 2006

AbstractThe absorption of bromhexine from Bromhexin tablets 8 mg, DAK has been compared with that from Bisolvon® tablets 8 mg, Boehringer Ingelheim, in a two‐way complete crossover study. Four tablets of each of the two bromhexine products, corresponding to a single dose of 32 mg of bromhexine hydrochloride (77.6 μmol), was administered to each of the 10 volunteers. The plasma concentration was followed over the 4‐hour period following each administration. By means of Pratt's test for paired data no statistically significant difference (p > 0.10) between the two products was found with respect to maximum plasma concentration (89 and 84nmol.l−1, respectively), the times for their occurrence (1.3 and 1.0h, respectively), and the area under the plasma concentration‐time curves (140 and 132 nmol.l−1.h, respectively). It is concluded that Bromhexin, DAK and Bisolvon® are bioequivalent.Provisional pharmacokinetic data for bromhexine, after oral administration, in man were obtained. The first‐pass effect and the biological half‐life were estimated by combining plasma and 30 h urine data from four of the volunteers. The first‐pass effect was estimated to be c. 75 per cent, the biological half‐life to be c. 6 h, and c. 0.1 per cent of the dose was found as unmetabolized bromhexine in the urine. The data indicate that the pharmacokinetics of bromhexine may be described as a two‐compartment open model.
Dose‐dependent pharmacokinetics of furosemide in the rat
Authors: Hammarlund M. M. , Paalzow L. K. 
Published: October 2006

AbstractThe pharmacokinetics of furosemide were investigated in the rat at doses of 10 and 40mg kg−1 corresponding to doses of 80 and 320 mg given to humans based on body surface area. A three‐compartment open model with renal excretion taking place from the shallow peripheral compartment gave the best fit to the data. The terminal half‐life of furosemide was found to change from 29min for the 10 mg kg−1 dose to 49min for the 40 mg kg−1 dose. This change could be detected as a change in the apparent volume of distribution caused by decreased protein binding at increasing plasma concentrations of furosemide. The total plasma clearance did not change significantly although metabolic and renal clearances both changed. The renal clearance was found to be dependent on the free fraction of furosemide in plasma and thus increased with increasing plasma concentrations. The metabolic clearance decreased with increasing dose indicating a saturable metabolism of furosemide.
Kinetics of cocaine in humans after intravenous and intranasal administration
Authors: Javaid J. I. , Musa Mahmoud N. , Fischman Marian , Schuster C. R. , Davis John M. 
Published: October 2006

AbstractCocaine kinetics were studied in four subjects after intravenous and intranasal administration. For intravenous administration cocaine hydrochloride (32 mg) dissolved in physiological saline was injected in 1 ml volume over a 1 min period. Intranasal cocaine was administered as 100mg powder consisting of an appropriate dose of cocaine hydrochloride (64 and 96 mg) mixed with lactose powder. Subjects were instructed to inhale the mixture through a 5 cm straw within 1 min. Cocaine kinetics, after intravenous injection, conform to a one‐compartment open model with first‐order elimination. After intranasal administration, cocaine kinetics conform to a one‐compartment model with first‐order absorpton and first‐order elimination. The mean half‐life of cocaine for intravenous injection in four subjects was 41·4±8·2 min (mean ± S.E.M.) and the range was 19 to 64min. There were statistically significant differences in the mean area under the concentration‐time curve (AUC) following intravenous and intranasal administration. The AUC was dose‐dependent and the fraction of the dose absorbed after 64mg intranasal cocaine was significantly lower than after 96 mg dose (p < 0·05).
Absorption of theophylline from enteric coated and sustained release formulations in fasted and non‐fasted subjects
Authors: Osman Mohamed A. , Patel Rajni B. , Irwin David S. , Welling Peter G. 
Published: October 2006

AbstractThe influence of prior food ingestion, and also of varying fluid volumes, on plasma theophylline levels was examined following single oral doses of two sustained‐release formulations, Theobid® (260 mg) and Theo‐Dur® (200 mg) and one partially enteric‐coated formulation, Choledyl® (128mg), to 9 healthy volunteers.Prior food ingestion tended to delay the absorption of theophylline from all formulations to a small extent. This effect was observed only at early sampling times, and plasma drug profiles were similar for all treatments within a particular formulation.Theobid® and Theo‐Dur® gave rise to plasma profiles that were characteristic of sustained‐release formulations, with mean Cmax values of 5·5−5·7 μgml−1 (Theobid®) and 2·8−3·2 μgmr−1 (Theo‐Dur®) occurring at 5·8−9·1 h after dosing. Choledyl® gave rise to a longer absorption lag time than the other formulations but was subsequently absorbed at a faster rate yielding mean Cmax values of 3·2−3·5μgml−1 at 2·8−4·1 h.The intersubject variability in theophylline plasma levels, and also in most pharmaco‐kinetic parameter values, was generally less following Theo‐Dur® compared to the other formulations.
Antipyrine metabolite kinetics in rats: Studies on dose and time dependence
Authors: Rhodes John C. , Houston J. Brian 
Published: October 2006

AbstractAntipyrine metabolite kinetics have been investigated in the rat with respect to dose and time dependence. The metabolic pathways, 4‐hydroxylation, benzylic oxidation, and N‐demethylation, are of equal quantitative importance (approximately 20 per cent of dose) and show no dose dependence over the range 25–500 mg kg−1. By using [N‐methyl‐14C]‐antipyrine the single carbon fragment lost by N‐demethylation may be monitored as 14CO2. Serial sampling of 14CO2 exhalation rate provides a half‐life estimate which, according to theoretical principles, reflects the antipyrine plasma half‐life. When both half‐lives were measured in the same animals a statistically significant correlation was evident. At doses of 250 mg kg−1 and 500mg kg−1 there is an increase in CER half‐life (218 and 303 min respectively) when compared to a dose below 100mg kg−1 (152 min). The metabolite formation rate constants are decreased accordingly at the high doses but are invariant over the dose range 25–100mg kg−1. Although inter‐rat variation in antipyrine metabolite kinetics was substantial, intra‐rat variability was small. The non‐invasive nature of determining antipyrine metabolite kinetics via breath and urine analysis provides a potentially useful animal model system to investigate the factors influencing hepatic mixed function oxidase activity in vivo.
Urinary pH and plasma levels of salicylate after administration of different buffered acetylsalicylic acid formulations
Authors: Bogentoft C. , Dahl G. , Magnusson A. 
Published: October 2006

AbstractIn a controlled cross‐over study comprising eight healthy subjects of effervescent acetylsalicylic acid (ASA) and an experimental ASA formulation were compared with unbuffered ASA and placebo concerning effects on the urinary pH within a dosage interval after 2 days' medication with 3 g ASA daily. The effects on the urinary pH were related to the morning plasma salicylate concentrations observed.Both the buffered formulations significantly increased the median pH of the period studied compared to unbuffered ASA, the effervescent by 1·5 units and the experimental by 0·6 units. Unbuffered ASA significantly decreased the median pH compared to placebo. Those subjects with the most acidic urine during placebo treatment showed the most pronounced pH elevations due to effervescent ASA. The plasma salicylate concentration was significantly lower with the effervescent formulation compared with unbuffered ASA, but there was no statistical difference between the experimental tablet and unbuffered ASA.The variable effects on the urinary pH and the plasma salicylate concentrations induced by the two buffered preparations are explained by the different absorbabilities of the buffering agents included. The results presented are consistent with recommendations not to use bicarbonate‐containing ASA formulations continuously when high plasma levels are desirable.
Steady‐state distribution volume in physiologic multi‐organ systems
Authors: Weiss Michael 
Published: October 2006

AbstractA unique definition of the apparent volume of distribution at steady‐state is presented which is consistent with the realistic concept of blood concentration differences within the circulatory system. A physiologically based pharmacokinetic model consisting of eliminating and non‐eliminating organs is used to predict the effect of drug elimination upon the steady‐state distribution volume.
The Statistical Package for the Social Sciences (SPSS) as an adjunct to pharmacokinetic analysis
Authors: Mather Laurence E. , Austin Kevin L. 
Published: October 2006

AbstractComputer techniques for numerical analysis are well known to pharmacokineticists. Powerful techniques for data file management have been developed by social scientists but have, in general, been ignored by pharmacokineticists because of their apparent lack of ability to interface with pharmacokinetic programs. Extensive use has been made of the Statistical Package for the Social Sciences (SPSS) for its data handling capabilities, but at the same time, techniques have been developed within SPSS to interface with pharmacokinetic programs of the users' choice and to carry out a variety of user‐defined pharmacokinetic tasks within SPSS commands, apart from the expected variety of statistical tasks. Because it is based on a ubiquitous package, this methodology has all of the benefits of excellent documentation, interchangability between different types and sizes of machines and true portability of techniques and data files. An example is given of the total management of a pharmacokinetic study previously reported in the literature by the authors.
Effect of food and an antacid on quinidine bioavailability
Authors: Ace Louis N. , Jaffe James M. , Kunka Robert L. 
Published: October 2006

AbstractTwo 200 mg quinidine sulfate tablets were administered to nine healthy male subjects in the fasting state, immediately after a balanced meal, and with 30ml of aluminum hydroxide gel using a complete crossover design. Serum and urine samples were taken over 32 and 60 h respectively. Quinidine concentrations were measured using a high‐performance liquid chromatography assay specific for quinidine. Computer fitting of the data to several models indicated that a one‐compartment model with zero‐order absorption and a lag time best fit all the data. Quinidine elimination and urine pH were unaffected by the study conditions. While the maximum serum concentration (Cmax) and area under the serum concentration—time curve (AUC) were unaffected by administration of quinidine with food or antacid, there was a 44 per cent increase (p < 0·10) in time to Cmax (tmax) following quinidine administration with food. Thus, while the extent of quinidine absorption was unaffected by food or the antacid used, the rate of quinidine absorption was significantly reduced by food as reported earlier.
Rectal versus oral absorption of codeine phosphate in man
Authors: Moolenaar Frits , Grasmeijer Germ , Visser Jan , Meijer Dirk K. F. 
Published: October 2006

AbstractRectal absorption of codeine phosphate from various dosage forms was studied in man. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. The plasma concentrations of codeine were measured by means of HPLC analysis after a single dose of 60 mg codeine phosphate in a cross‐over study in 7 volunteers. Compared with oral dosing rectal absorption from an aqueous solution or a fatty suppository produced an almost identical plasma concentration profile with similar interindividual variations. Comparing the absorption rate characteristics it appeared that rectal absorption from an alkaline solution containing codeine phosphate proceeded significantly (P < 0·05) more rapid than after oral dosing. No essential difference in bioavailability was observed between the various rectal and oral dosage forms.