bluuebunny/crossref_metadata_2025_split huggingface dataset:
The relationship between buspirone bioavailability and dose in healthy subjects
Authors: Gammans R. E. , Mayol R. F. , MacKenthun A. V. , Sokya L. F. 
Published: October 2006

AbstractDose dependency of the pharmacokinetics of buspirone, a new anxiolytic agent, was tested in 24 healthy volunteers. Each subject received 10, 20, and 40 mg doses according to a randomized, three‐way crossover design with a 7‐day interval between treatments. Buspirone AUC values at 10, 20, and 40 mg doses were in the ratio of 1:1.7:3.5 while Cmax values, had a ratio of 1:1.9:3.7. The dose normalized (10 mg basis) AUC and Cmax values, Tmax values, and half‐lives were not significantly different (p > 0.05) among the doses. Buspirone half‐life did not change as a function of dose (mg kg−1). It was concluded that buspirone exhibits linear pharmacokinetics following doses in the therapeutic range.
Pharmacokinetics and pharmacodynamics of bromocriptine in the rat
Authors: Schran H. F. , Tse F. L. S. , Bhuta S. I. 
Published: October 2006

AbstractThe absorption, distribution, and excretion of bromocriptine were studied following oral and parenteral administration of non‐radioactive and 14C‐labelled drug in the rat. Total radioactivity was measured in blood, tissues, and excreta by liquid scintillation counting while the parent drug was determined in plasma and selected tissues by radioimmunoassay. The pharmacokinetic observations were compared with the time course of drug‐induced hypothermia in cold‐room acclimatized rats. The results indicated that oral doses of bromocriptine were rapidly, though incompletely (32‐40 per cent), absorbed, but underwent extensive first‐pass metabolism, resulting in an absolute bioavailability of only 6 per cent. The bioavailability increased to approximately 22 per cent in rats pretreated with the hepatic microsome inhibitor proadifen, thus suggesting the liver as the principal site of biotransformation. Absorbed bromocriptine showed preferential distribution into the tissues, although no apparent accumulation of drug‐related material occurred in the body. The drug was eliminated almost exclusively by metabolism and biliary excretion into the faeces. Comparison of the pharmacodynamic and the pharmacokinetic profiles indicated a dose relationship between hypothermia and plasma bromocriptine concentrations but not total radioactivity levels. The hypothermic response was also intensified by proadifen pretreatment, thus confirming the parent drug as the pharmacologically active entity. It is believed that the previously reported delay in the onset of bromocriptine activity is not pharmacokinetic in nature, but is related to the properties of the receptors at the target site or to the pharmacologic events that result in the observed effects.
Pharmacokinetics of prednisolone after high doses of prednisolone hemisuccinate
Authors: Derendorf H. , Rohdewald P. , Möllmann H. , Rehder J. , Barth J. , Neveling D. 
Published: October 2006

AbstractPrednisolone in the form of its hemisuccinate was given intravenously in two different doses (1200 mg and 75 mg). Plasma levels of the ester and prednisolone were measured and pharmacokinetic parameters were calculated. The results indicate a dose‐dependency in the pharmacokinetics of both hemisuccinate and the free alcohol. For the high dose 8 per cent of the administered ester was found unchanged in the urine indicating incomplete conversion of the pro‐drug. Comparison with previous studies leads to the conclusion that prednisolone shows doubled non‐linear pharmacokinetics with higher total body clearance in the medium dose range than in the low and high dose range. Volume of distribution changes accordingly, but overall elimination rate remains remarkably constant. Saliva levels of prednisolone were low and agree reasonably well with calculated plasma concentrations of free, non‐proteinbound prednisolone. No prednisolone hemisuccinate was found in saliva.
Effects of phenobarbital steady state levels on antipyrine clearance and distribution in the rat
Authors: Pei Yuan‐Ying , Bialer Meir , Levy René H. 
Published: October 2006

AbstractA group of 15 rats received two intravenous bolus doses of antipyrine (15 mg/kg) separated by a 57 hour infusion (with bolus dose) of phenobarbital. Phenobarbital bolus doses and infusion rates were based on a preliminary pharmacokinetic study (7 rats) and were varied to achieve a broad range of steady state levels. Antipyrine and phenobarbital blood levels were measured by high pressure liquid chromatography. Antipyrine kinetics obeyed first order monoexponential decay, and the parameters (clearance, volume, half‐life) were determined. Antipyrine clearance increased in all animals during phenobarbital infusions with a per cent increase ranging between 54·6 and 269 per cent. However, no significant correlation was found between the per cent increase in antipyrine clearance and phenobarbital concentration (r = 0·19). The volume of distribution of antipyrine increased in 14 of 15 animals with increases ranging between 7·7 and 45·8 per cent.
Evaluation of two new megestrol acetate tablet formulations in humans
Authors: Gaver R. C. , Pittman K. A. , Reilly C. M. , Goodson P. J. , Breault G. O. , Fenzl E. 
Published: October 2006

AbstractThe bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet (Megace®). The tablets were administered to 24 male subjects in a three‐way cross‐over study, balanced for sequence, with a week between administrations. The 40 mg tablets were administered q.i.d. at 08.00, 12.00, 18.00 and 22.00 h, while the 160 mg tablets were administered once at 08.00 h. Plasma samples were collected at appropriate times out to 96 h after administration and were analysed for megestrol acetate with a validated high performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2·5 to 2·8 h), the absorption rate constant was the same for each of the tablets. Relative to the 40 mg q.i.d. dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97 per cent and 118 per cent, respectively.
The pharmacokinetics of oral and intravenous prenalterol in young, healthy volunteers
Authors: Clarke A. F. , Jack D. B. , Kendall M. J. , Smith S. R. 
Published: October 2006

AbstractThe pharmacokinetics of prenalterol in healthy young volunteers after i.v. and oral dosing has been studied. There is evidence of non‐linearity following the i.v. dosing. Evidence of dose‐dependent pharmacokinetics following i.v. dosing has been obtained. The sustained‐release formulation is very effective: almost 12 h were needed to achieve 50 per cent of the total AUC.
The effect of administration of propranolol on the pharmacokinetics of isoxicam
Authors: Caillé G. , Larivière L. , Lacasse Y. , Vézina M. , Besner J. G. 
Published: October 2006

AbstractIn order to examine a potential interaction between isoxicam and propranolol, single 200 mg doses of isoxicam were administered to ten healthy male volunteers before and during treatment with propranolol, gradually attaining a dose of 80 mg t.i.d. for 11 days. The pharmacokinetic profiles of the isoxicam plasma concentration/time data obtained over 96 h following the doses of isoxicam before and during propranolol administration were compared. No significant change was found in any of the pharmacokinetic parameters determined. These results suggest that propranolol has no effect on the metabolic disposition of isoxicam.
Bioavailability of seven furosemide tablets in man
Authors: Straughn Arthur B. , Wood George C. , Raghow Gursharan , Meyer Marvin C. 
Published: October 2006

AbstractA seven‐way crossover study was conducted in 14 healthy male volunteers to evaluate the relative bioavailability of seven different marketed 40 mg furosemide tablets. Each dose was administered as a single tablet after an overnight fast, and blood samples were obtained for 16 hours. Plasma was assayed by HPLC. There were no statistically significant differences among the seven products for the mean peak concentration (1·01–1·29 μg/ml), mean time of peak (1·2–2·1 h) or mean area under the plasma concentration‐time curves, which differed by less than 14 per cent. However, one product exhibited greater intersubject variability, and on this basis was considered inequivalent to the other six products.Furosemide is a potent and widely used diuretic. Currently the United States Food and Drug Administration (USFDA) has granted approval to at least twelve manufacturers of 40 mg furosemide tablets, based in part on bioavailability data obtained in human subjects. In addition, the USFDA has granted an ‘AB’ therapeutic equivalence evaluation to each of these products.1 which is understood by many to indicate the therapeutic equivalence and interchangeability of these products.The objective of the present investigation was to directly compare the bioavailability of seven 40 mg furosemide tablet products which had previously been approved by the Food and Drug Administration.
Limitations of the MANOVA of statistical moments in bioequivalence trials of drugs with slow elimination rate: A study with spironolactone
Authors: Concheiro A. , Llabres M. , Martinez R. , Vila J. L. 
Published: October 2006

AbstractThe capacity of the statistical moments for detecting bioavailability changes in bioequivalence studies of drugs with high disposition mean residence time (MRT) is analysed. Two bioavailability trials were carried out with spironolactone in which extent and rate of absorption were modified in a controlled way. The statistical analysis employed was a two‐way MANOVA of statistical moments of the urinary excretion profiles of canrenone. The results indicate a loss in the sensitivity of MRT for detecting changes in absorption rate as drug elimination rate decreases.
Bioavailability of cyanamide in fasted and unfasted rats
Authors: Obach R. , Valenti C. , Valles J. , Valles J. M. , Domenech J. 
Published: October 2006

AbstractThe pharmacokinetics of cyanamide after 35 mg kg−1 intravenous and oral administration to fasted and unfasted rats have been investigated. The plasma level are fitted well by a two‐compartment open model. The half‐life (t1/2β) of cyanamide in the rat was 1 hour and the plasma clearance (C1p) was 0.02 (1 kg−1) min−1. Food does not appear to modify the absolute bioavailability of cyanamide (F = 93.3 per cent fasted, F = 85.5 per cent unfasted), although it does retard drug absorption.
Bioequivalency and dose proportionality of three tableted promethazine products
Authors: Zaman R. , Honigberg I. L. , Francisco G. E. , Kotzan J. A. , Stewart J. T. , Brown W. J. , Shah V. P. , Pelsor F. R. 
Published: October 2006

AbstractData from a five‐way crossover study in human subjects using four talented promethazine products and a promethazine solution are presented. All products were administered as a single oral dose. The five objectives of the study were to investigate bioequivalency, to estimate dose proportionality at two dose levels, to establish validity of a reference production solution for future bioequivalency studies, to estimate intersubject variation, and to compare bioavailability/tablet dissolution data. Blood samples were collected at given intervals over a 24‐hour period and analysed for promethazine using an HPLC technique. Pharmacokinetic parameters were calculated using standard procedures and a two‐way analysis of variance (ANOVAR) was used to assess whether the differences were statistically significant. The AUC0→∞ data from the ANOVAR analysis showed that the 50 mg innovator and generic products and the 50 mg solution were not significantly different. However, the innovator product had a significantly lower Cmax and longer tmax than the solution. The generic product did not differ significantly from the solution. Promethazine was found to exhibit linear dose proportionality in the range and product studied. Intersubject variation was high for all parameters (23 to 63 per cent) and the in vivo and in vitro data showed a positive relationship.
Comparative physiological disposition of two nitrofuran anti‐microbial agents
Authors: Labaune J. P. , Moreau J. P. , Byrne R. 
Published: October 2006

AbstractThe physiological disposition of two nitrofuran derivatives used as antimicrobial agents for the treatment of acute infectious diarrhea was evaluated in humans and animals. Upon administration of a single oral dose (600mg) of nifurzide or nifuroxazide, no unchanged parent drug was detected in human blood or urine. In rats given 14C‐nifurzide and 14C‐nifuroxazide at a dose of 10mg kg−1, 5 per cent and 17 per cent of the dose of nifurzide and nifuroxazide, respectively, were excreted in urine over a 48‐hour period. None of this radioactivity was present as unchanged drug, indicating that renal excretion of both drugs occurs as metabolites. In the feces 20 per cent of the radioactivity recovered was associated with unchanged nifuroxazide as compared with 100 per cent for nifurzide. Whole body autoradiography using rats showed that after oral administration of 14C‐nifurzide and 14C‐nifuroxazide, most of the radioactivity remained in the gastrointestinal lumen.
Preparation and disposition of asialofetuin‐labelled liposome
Authors: Tsuchiya Seishi , Aramaki Yukihiko , Hara Toshifumi , Hosoi Kaoru , Okada Akira 
Published: October 2006

AbstractA liposome labelled with asialofetuin(AF‐liposome) was prepared by the detergent dialysis method. Asialofetuin in the amount of 34–68 μg were imposed among the 1 μM of phospholipids constituting the outer surface of liposome. The AF‐liposome containing [14C]‐cholesterol in the lipid layer and [3H]‐sucrose in the aqueous layer was intravenously administered to rats. Both radioactivities were biphasically cleared from systemic circulation at rates faster than that of the fetuin‐labelled liposome. These radioactivities were recovered in the liver by about 90 per cent within 60 min, and per gram of tissue, were highest in this organ. In an in vitro experiment using isolated rat hepatocytes, the high affinity of the AF‐liposome toward hepatocytes was observed from scanning electron micrographs. Based on these findings, the AF‐liposome may possibly be stable in circulation and function as a carrier of encapsulated drugs to hepatocytes.
Plasma concentrations and bioavailability of propranolol by oral, rectal and intravenous administration in man
Authors: Cid Edison , Mella Fernando , Lucchini Leonardo , Cárcamo Martín , Monasterio José 
Published: October 2006

AbstractEight normal male volunteers received 80 mg doses of propranolol by the oral and rectal routes and 2·2 mg by intravenous administration in a crossover fashion. Plasma concentrations of propranolol were measured by a gas chromatographic method using an electron capture detector. Individual subject concentration–time data were analysed and results indicated that the data fit a two compartment model with first order absorption. An approximately two‐fold higher plasma propranolol concentration was observed after rectal administration as compared with oral dosing. Statistical analysis of the difference in the total AUCs indicates a significantly higher bioavailability of propranolol administered by the rectal route. The reduced bioavailability after oral administration indicates a substantial first pass effect but that it is possible to bypass the liver, at least partially, by giving the drug rectally to man.
Correlation between inhibitory effect on platelet aggregation and disposition of sulfinpyrazone and its metabolites in rabbits. Part I: Single dose study
Authors: Ritschel Wolfgang A. , Kuo Be‐Sheng 
Published: October 2006

AbstractSimultaneous evaluation of inhibition of the sodium arachidonate‐induced platelet aggregation and drug disposition was studied in rabbits receiving single doses of sulfinpyrazone (SO) and its sulfide metabolite (S). The metabolism of SO was found to be interconversible with that of S. Due to the parallelism of disposition profiles, the observed concentration‐related inhibition not only strongly correlated with the much more potent sulfide, but also correlated with the p‐OH‐sulfide (OH‐S) or with a summation of two substances. Exaggeration of inhibition at 24–30h and rebound effect at 48h were found after the substances were administered. There may exist a circadian rhythm of platelet aggregation.
The bioavailability of oral nifedipine formulations: A statistical and simulation approach
Authors: Kozjek F. , Primozic S. , Mrhar A. , Karba R. , Raemsch K. D. , Janezic A. 
Published: October 2006

AbstractThe bioequivalence of three oral forms of nifedipine was assessed in a triple crossover study on 12 healthy volunteers. Single 10 mg dose was given and ten blood samples were drawn during the first 8 h after administration. Highly sensitive gas chromatographic method was used for the nifedipine assay. Pharmacokinetic parameters which describe bioavailability and general kinetic behaviour of the drug (AUC, Cmax, tmax, beta, MRT) were calculated from individual plasma profiles. They were subjected to statistical analysis (paired t‐test, Hauck's inverted t‐test, and Westlake's method of confidence intervals). Analogue‐hybrid simulation and identification was used to generate plasma profiles of nifedipine after single and multiple dosing. Averaged plasma concentrations were used for this purpose. The three formulations studied were bioequivalent in terms of the rate of absorption. The simulation proved to be an efficient tool to substitute in vivo multiple dosing studies for assessment of bioavailability. The specific statistical methods should be preferred in bioequivalence data evaluation due to their greater power and inclusion of extraneous bioequivalence limits interval. Despite the differences among the formulations studied, each one of them should be viewed according to its intended clinical use.
Method of residuals: Estimation of absorption and elimination rate constants having comparable values
Authors: Macheras P. 
Published: October 2006

AbstractAn equation was developed to be used with the method of residuals for the analysis of the linear one‐compartment open model. This equation can provide information about the magnitude of the ratio of rate constants, without assuming that the terminal phase reflects solely either an elimination or an absorption process, as must be done for the graphical techniques. It also enhanced the analytical power of the method of residuals in that it gave better estimates of the absorption rate constant when the latter and the elimination rate constant have comparable magnitudes.
Lack of effect of multiple doses of cimetidine on estimated hepatic blood flow
Authors: Grasela Dennis M. , Rocci Mario L. , Rotmensch Heschi H. , Vlasses Peter H. 
Published: October 2006

AbstractConflicting data exists regarding the effect of the H2‐receptor blocking agent cimetidine on hepatic blood flow (HBF). The variance in the results of these studies may be due in part to differences in the duration of cimetidine administration, the posture of the volunteers during their course of study, and the method used to estimate HBF. To assess the effects of chronic cimetidine (300 mg q.i.d. × 4 days) on estimated HBF while controlling posture (supine and standing), a double‐blind, placebo‐controlled, repeated measures study was performed in 9 healthy males. Indocyanine green (ICG) plasma clearance after an i.v. dose of 0.5 mg kg−1 was used to calculate HBF. ICG plasma concentrations were measured by HPLC. Compared to placebo treatment, cimetidine had no effect on mean (SD) estimated HBF (ml min−1 m−2) in either the supine (497 (64) vs 494 (80)) or the standing (443 (117) vs 404 (89)) posture. These data had a power > 0.8 to detect a treatment effect of 20 per cent. Standing produced a significant decrease in estimated HBF (496 (70) vs 424 (102); p < 0.01). In contrast to previous reports, chronic cimetidine treatment had no apparent effect on hepatic blood flow.
Prediction of drug distribution in vivo on the basis of in vitro binding data
Authors: Schuhmann G. , Fichtl B. , Kurz H. 
Published: October 2006

AbstractFor 11 drugs it was investigated whether tissue distribution in vivo can be predicted by use of binding data obtained in vitro. The selection of drugs represented a broad spectrum of physicochemical and pharmacokinetic properties thought to be important for distribution of drugs in vivo. The extent of binding to plasma and to tissue‐homogenates of rabbits was determined in vitro. The drug concentrations in plasma, liver, lungs, kidneys, and skeletal muscle of rabbits were determined in vivo after i.v. administration of the drug. The tissue‐plasma partition ratios measured in vivo were compared with the theoretical tissue‐plasma partition ratios calculated from the in vitro binding data.For all drugs investigated the muscle‐plasma partition ratio could be reasonably well predicted by the in vitro binding data. In liver, lungs, and kidneys good agreement was found between measured and predicted tissue‐plasma ratio for anionic drugs; marked differences, however, were observed between measured and predicted tissue‐plasma ratios of lipophilic cationic drugs. A significant correlation was found between binding of drugs to muscle tissue in vitro and the volume of distribution of the unbound drug (Vf), opening the possibility to approximate Vf from in vitro binding studies with rabbit muscle tissue.
Pharmacokinetics of tiazofurin in dogs
Authors: Obeng E. K. , Vallner J. J. , Cadwallader D. E. , Tackett R. L. 
Published: October 2006

AbstractThe pharmacokinetics of total and free tiazofurin, an antineoplastic agent, was studied in healthy mongrel dogs following intravenous and oral administration of the drug. The free fraction of tiazofurin was obtained from plasma by an ultrafiltration technique using a micropartition system. Total and free tiazofurin levels were determined by a sensitive high performance liquid chromatographic method. The percentage of tiazofurin bound to plasma proteins remained constant at approximately 15 per cent following administration to healthy mongrel dogs. The mean pharmacokinetic parameters of elimination rate constant (K), effective half‐life (t1/2), mean residence time (MRT) and the time to reach peak plasma level (tmax—after oral administration) were 0.32 ± 0.04 h−1, 2.24 ± 0.25 h, 3.23 ± 0.36 h, and 1.78 ± 0.50 h, respectively. The apparent volume of distribution at steady state was 0.98 ± 0.30 I kg−1 and the plasma clearance was 5.24 ± 2.39 ml min−1 kg−1. About 90 per cent of tiazofurin was absorbed following oral administration. The pharmacokinetic parameters did not differ significantly between the total and free drug levels, indicating that the pharmacokinetics of total tiazofurin levels reflect those of the free tiazofurin in plasma.