bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single oral dose proportionality pharmacokinetics of almitrine bismesylate in humans
Authors: Stavchansky S. , Doluisio J. T. , MacLeod C. M. , Szalkowski M. B. , Bachand R. T. , Heilman R. , Sebree T. B. , Geary R. S. 
Published: October 2006

AbstractA single‐blind study was conducted in 10 healthy male subjects. Each subject was tested with four single oral doses of capsules containing 25, 50, 100, 200mg almitrine bismesylate and one dose of placebo. Blood samples were drawn as a function of time and the concentration of almitrine in plasma was determined by gas chromatography utilizing nitrogen‐phosphorus detection. Linear regression analysis of the data suggested that a deviation from linearity existed between the area under the plasma concentration time curves and the dose (R = 0·96). Linear analysis of the individual data indicates that a slight negative deviation from linearity is apparent for the 200mg dose, The same trend was observed for the mean maximum almitrine plasma concentration, Cmax, which ranged from 38·9 ± 11·8 to 286·2 ± 99·1 ngml−1 for the 25 and 200mg dose, respectively. The time to peak was relatively constant regardless of the administered dose and ranged from 2·4 ± 0·5h to 2·8 ± 0·8h. Good agreement was obtained between the observed bioavailability parameters and those predicted from the nonlinear fit of the data. Further kinetic analysis of the data revealed mean total body clearance over fraction of dose absorbed ranging from 268·2 ± 132·8 to 436·4 ± 191·4 ml min−1 for doses 50 and 200mg, respectively.
Evidence of a specialized transport mechanism for the intestinal absorption of baclofen
Authors: Merino M. , Peris‐Ribera J. E. , Torres‐Molina F. , Sánchez‐Picó A. , Garćia‐Carbonell M. C. , Casabó V. G. , Martín‐Villodre A. , Plá‐Delfina J. M. 
Published: October 2006

AbstractAbsorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats in situ, is shown to be a specialized transport mechanism obeying Michaelis‐Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis‐Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yielded Vm and Km values of 12·0mgh−1 and 8·0mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but comparable absorption rates were found in the proximal and distal segments of the small intestine, whereas in colon, drug absorption was negligible. Baclofen transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. If these results were extrapolated to humans, they would explain the excellent bioavailability profiles reported for baclofen at normal doses in spite of its physicochemical properties, which do not favour passive diffusion. Based on the same principle, the administration of usual doses at shorter time intervals could be recommended, instead of high, when higher plasma levels at steady‐state are needed. On the other hand, more than 8‐h sustainedrelease preparations of baclofen should, probably, be avoided.
In vitro and in vivo evaluation of seven 50 mg and 100 mg nitrofurantoin tablets
Authors: Meyer Marvin C. , Wood George C. , Straughn Arthur B. 
Published: October 2006

AbstractFour 50 mg and three 100 mg marketed nitrofurantoin tablets were studied in 14 healthy male subjects. Urine was collected 1, 2, 3, 4, 6, 8, 12, and 23 h after each dose, and nitrofurantoin was assayed by HPLC. The in vitro dissolution of the tablets was determined using USP Apparatus 1 and 2, with 0·1 N hydrochloric acid and pH 7·2 buffer as the dissolution fluids. One of the 50 mg tablets was more rapidly and completely absorbed than the other six products. The incidence of side‐effects for this product was as low or lower than the other products. It was determined that the use of the USP Apparatus 1, at 100 rev min−1, with sampling of the pH 7·2 fluid at 30 min, provided for the best overall relationship between the urinary excretion and in vitro dissolution.
Buffering the stomach content enhances the absorption of diflunisal in man
Authors: Nuernberg Bernd , Brune Kay 
Published: October 2006

AbstractDiflunisal, a lipophilic salicylate, is absorbed more slowly in healthy volunteers than aspirin. In this paper we report on attempts to influence diflunisal absorption by buffering the gastric milieu. Sodium bicarbonate given together and 30 min after diflunisal tablets significantly (p < 0·05) shortened the time to reach peak plasma concentration (tmax > 15 per cent), raised maximum plasma concentration slightly (Cmax 6 per cent) and increased the area under the plasma concentration‐time curve (AUC > 8 per cent). Other pharmacokinetic parameters, including terminal half‐life and renal elimination of the compound, were not considerably influenced. These findings indicate that the absorption of diflunisal was enhanced by increased gastric pH, presumably a result of an increased solubility of diflunisal in the stomach together with faster transport into the small intestine.In one volunteer, after intravenous administration diflunisal plasma concentrations declined in a triphasic manner with a terminal half‐life of 12·8 h. The volume of distribution was approximately 10 per cent of body weight. Based on the ratio of AUC after equivalent i.v. and oral diflunisal doses, the absolute bioavailability was 89·5 per cent.
Gastrointestinal, liver, and lung extraction ratio of acetaminophen in the rat after high dose administration
Authors: Bhargava v. O. , Hirate Junji 
Published: October 2006

AbstractThe pharmacokinetics of acetaminophen was examined in rats after administration of a single dose of 200 mg kg−1 by the intra‐arterial, intravenous, portal vein, and oral routes. Levels of acetaminophen and its two major metabolites, acetaminophen‐glucuronide and acetaminophen‐sulfate, were quantitated in plasma at various time points for about 5 h after drug administration. The relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction ratio (first‐pass effect after oral absorption) was determined. A mean oral extraction ratio of 0·49 was obtained. The mean relative extraction ratio of the gastrointestinal tract, liver, and lung were 0·52, 0·07, and 0, respectively, indicating a major contribution due to the gastrointestinal tract. This is in contrast to earlier studies which have indicated negligible contribution by the gastrointestinal tract to the oral first‐pass effect when lower doses were utilized. These results suggest that the relative contribution of the gastrointestinal tract and liver to the oral first‐pass effect of acetaminophen may be dose‐dependent.
Pharmacokinetics of lisinopril (IV/PO) in healthy volunteers
Authors: Beermann Bjorn , Till Alice E. , Gomez Hector J. , Hichens Martin , Bolognese James A. , Junggren Inga‐Lill 
Published: October 2006

AbstractWhen three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin‐converting enzyme (ACE). The half‐life for the terminal phase (approximately 40 h) was not predictive of steadystate parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half‐life for accumulation was 12·6h. The mean accumulation ratio was 1·38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril maleate.
Competitive binding of sulfamethazine and its N‐acetylated metabolite
Authors: Tsang Y‐C. , Thiessen J. J. 
Published: October 2006

AbstractThe protein binding of sulfamethazine (SMZ) was studied in rabbit serum. Serum solutions comprising various concentrations (∼0·01 – 3mM) of SMZ and its major metabolite, N4‐acetylsulfamethazinc (AcSMZ), were prepared. These ‘control’ samples were also mixed via a Latin square design to study the interactive binding of SMZ and AcSMZ to the proteins. Equilibrium dialysis was conducted for 8 h.Post‐dialysis measurement of SMZ/AcSMZ radioactivity in the buffer and serum chambers provided the free and bound fractions based upon equilibrium total serum concentrations. There was no significant change of protein concentration before and after dialysis. The ‘control’ data revealed concentration‐dependent binding for both drugs while the interaction study clearly indicated the presence of competitive binding. Scatchard plots suggested the presence of more than one binding site. As a result, three different competitive binding models were examined via computer analysis of the observations. The most appropriate binding model was identified to consist of specific binding (protein concentration, Pt; dissociation constant, Kd) and nonspecific binding (Nsp). The mean (SD) ‘control’ parameter estimates for PtSMZ, PtAcSMZ, KdSMZ, KdAcSMZ, NspSMZ, NspAcSMZ were: 0·562(0·041), 0·605(0·024), 0·078(0·006), 0·031(0·002) [mM], 0·205(0·054), and 0·229(0·043), respectively. In the interaction study these values were: 0·599(0·022), 0·479(0·019), 0·091(0·004), 0·023(0·001), 0·228(0·020), and 0·434(0·061), respectively. The findings indicate that both drugs bind to albumin but the affinity of AcSMZ is greater than SMZ. Theoretically, the metabolite can therefore alter the in vivo SMZ binding thereby in turn causing apparent nonlinear acetylation based upon the pharmacokinetics of total SMZ concentrations.
Relationships between steady‐state and single‐dose plasma drug concentrations for pharmacokinetic systems with nonlinear elimination
Authors: Cheng Haiyung , Jusko William J. 
Published: October 2006

AbstractEquations were examined to predict or correlate steady‐state (SS) plasma concentrations and single‐dose (SD) data for pharmacokinetic systems with various types of input and nonlinear elimination. The effects of variation of the Michaelis‐Menten parameters, input rate of drug, or bioavailability on the predictability of steady‐state plasma concentrations from single‐dose data were demonstrated by computer simulations for a one‐compartment model. Use of apparently linear equations with Michaelis‐Menten parameters to predict steady‐state plasma concentrations from single dose data is adequate only in limiting low single‐dose cases. Linear SS versus SD correlations for both intravenous and oral dosing can be observed in population data only when Km is the principal variable; other conditions produce curvilinear behavior. Equations to calculate values of the Michaelis‐Menten parameters from dual single‐dose and steady‐state AUC values are derived and tested for drugs which are intravenously administered. These equations and simulations provide insight into factors determining the relationship between SS and SD AUC for drugs with nonlinear elimination.
Stability, human blood distribution and rat tissue localization of promazine and desmonomethylpromazine
Authors: Hu Oliver Y‐P. , Curry Stephen H. 
Published: October 2006

AbstractThe stability in human blood and urine, partitioning into red blood cells and plasma protein binding of promazine and desmonomethylpromazine were investigated. Tissue localization was investigated in rats. Promazine and desmonomethylpromazine were stable in human plasma and urine for at least 64 days at −20°. The percentage of promazine not bound to protein in plasma was 10·4 ± 2·43 as estimated by equilibrium dialysis with correction for volume shift, and 11·6 ± 0·43 per cent as estimated by ultracentrifugation. Data for the mean plasma/red blood cell concentration ratio and the red blood cell/plasma distribution coefficient for promazine were 1·19 ± 0·13 and 8·21 ± 0·40, respectively. There was no evidence of time‐dependence in plasma/red blood cell partitioning. Ten rat organs and tissues were examined. The concentrations of promazine and desmonemethylpromazine were highest in lung. For promazine, the rank order of tissue localization was lung > liver > kidney > intestine > brain > spleen > red blood cell > voluntary muscle > plasma > stomach > heart. For desmonomethylpromazine, the order was reversed in the cases of spleen and brain and interchanged in the cases of stomach and muscle. The brain/plasma concentration ratios for promazine and desmonomethylpromazine in rat were 4·69 and 3·87, respectively.
Effects of obesity and ancillary variables (dialysis time, drug, albumin, and fatty acid concentrations) on theophylline serum protein binding
Authors: Shum Linyee , Jusko William J. 
Published: October 2006

AbstractThe effect of obesity on the serum protein binding of theophylline was investigated in man and rat along with other ancillary variables such as dialysis time, theophylline concentration, albumin concentration, and fatty acid type and concentration. The per cent binding of theophylline first increased with dialysis time, reached equilibrium over 2 to 6 h, then diminished. This decrease was not due to instability of theophylline. Theophylline binding was linear over a concentration range of 15 to 150 μg ml−1. A similar degree of binding was found in normal humans (44·4 ± 1·0%) and rats (41·5 ± 0·5%). The binding ratio (bound/free) of theophylline was proportional to the albumin concentration (1 to 5%) and yielded a binding parameter (NK) of 1·47 × 10−3 M−1. Over a normal physiological range, individual and mixed fatty acids had minimal effects on theophylline binding to albumin. However, binding significantly decreased as fatty acid (FFA) concentrations increased. The magnitude of the effect appeared to parallel the carbon chain number of the fatty acid. Theophylline binding in obese subjects decreased to a mean (SD) of 35·8 ± 8·0 per cent compared to 43·0 ± 6·1 per cent in normal subjects (p < 0·05). Similar decreases were found in normal versus obese rats and in the saliva: serum ratio following theophylline administratin to normal and obese human subjects. Obesity causes a moderate decrease in serum binding of theophylline which may be attributed to increased FFA rather than in vitro artifacts.
Bioinequivalence of a generic brand of diazepam
Authors: Locniskar Ann , Greenblatt David J. , Harmatz Jerold S. , Shader Richard I. 
Published: October 2006

AbstractTwenty‐six healthy male volunteers received a single 10 mg dose of diazepam on two occasions in a crossover bioequivalence study comparing the reference product (Valium) and a generic formulation (NeoCalme). Concentrations of diazepam and its metabolite, desmethyldiazepam, were determined during 264 h after each dose. Peak plasma diazepam concentrations were significantly lower for NeoCalme vs Valium (247 vs 394 ng ml−1, p < 0·001) and reached significantly later after the dose (1·62 vs 0·98 h, p < 0·001). Total area under the plasma concentration curve (AUC) was also significantly lower for NeoCalme (6614 vs 7552 ng ml−1 × h, p < 0·001), although AUC ratios for NeoCalme divided by Valium satisfied the ‘75–75’ guidelines. Findings for desmethyldiazepam were similar. Thus, diazepam absorption from the generic brand of diazepam is significantly slower than from Valium, which in turn could lead to therapeutic inequivalence.
Absorption and disposition kinetics of chlorothiazide in protein‐calorie malnutrition
Authors: Jung Donald , Lam Hue Di , Chu Michael 
Published: October 2006

AbstractThe influence of dietary protein deficiency on the absorption and disposition kinetics of chlorothiazide was investigated in male Sprague‐Dawley rats fed for 4 weeks on a 23 per cent (control) or a 5 per cent (low) protein diet ad libitum. Chlorothiazide in plasma and urine was determined by a sensitive and specific HPLC assay. Following an intravenous dose of 10mgkg−1 chlorothiazide, there was a significant decrease in the total plasma clearance (Cl) per kg of body weight from 1·80 ± 0·15 to 1·29 ± 0·15 1 h−1 kg−1 and apparent steady‐state volume of distribution from 0·65 ± 0·13 to 0·38 ± 0·071 kg−1 in the protein‐deficient rats. However, no significant difference was found in the two groups of animals with respect to mean residence time (MRT) and free fraction of drug in plasma. The mean harmonic half‐life was increased from 72 to 91 min in the protein‐deficient rats. The urinary recovery of unchanged chlorothiazide in 48 h was essentially complete in both groups of animals. The absorption of chlorothiazide, as assessed by the mean urinary recovery of unchanged drug after oral administration, was 66 per cent and 68 per cent in normal and protein‐deficient rats, respectively.
A new approach to pharmacokinetic parameters: Estimation of cefuroxime during haemodialysis
Authors: Sanchez Esther , Evora Carmen Ma , Torres Armando , Llabres Matias 
Published: October 2006

AbstractA linear three‐compartment model is proposed as a means of estimating disposition and extracorporeal elimination pharmacokinetic parameters during haemodialysis. It was created by connecting a compartment, corresponding to the amount of drug present in the dialysis cell, to the central compartment of the standard two‐compartment model from which elimination would normally take place. The transfer rate constants between the central compartment and the ‘dialysis cell’ and vice versa were given in terms of the plasma flow, central compartment volume, and volume of plasma contained in the dialysis cell, and thus cannot be considered to be independent parameters. The product of the rate constant for elimination from the dialysis cell, k30, and the plasma volume within the cell was used to quantify the extracorporeal elimination and termed intrinsic dialyser clearance, CLint,D. The model was used to interpret the plasma level curves obtained after administering 750 mg cefuroxime by IV bolus to a group of patients undergoing haemodialysis. The distribution parameters estimated by non‐linear regression were similar to those given in the literature; however, in five of the twelve cases, no estimate of cefuroxime elimination from the central compartment (k10) could be derived. On the other hand, the estimates of the elimination rate constant (k30) from the deep peripheral compartment were greater than the values given in the literature, ranging from 50·6 h−1 to 151·0 h−1 and CLint,D ranging from 3·1 h−1 to 8·90 lh−1.The error in measuring the flow of plasma which reaches the dialyser, its influence upon the estimation of the model parameters and the relationship between the parameters themselves and those customarily used in the study of drug haemodialysis are all discussed.
Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration
Authors: Scavone Joseph M. , Luna Becki G. , Harmatz Jerold S. , von Moltke Lisa , Greenblatt David J. 
Published: October 2006

AbstractEight healthy volunteers received 50 mg of dimenhydrinate, a theoclate salt of diphenhydramine, orally, sublingually, and intravenously on three separate occasions in random sequence. Plasma diphenhydramine concentrations during 12 h after each dose were measured by gas‐liquid chromatography with nitrogen‐phosphorous detection. Mean peak plasma concentrations after sublingual administration were slightly lower than after oral dosage (38·3 vs 47·8 ng ml−1), and the time of peak concentration was similar (2·6 vs 2·3 h after dose). These differences did not reach statistical significance. The mean total area under the plasma concentration‐time curve (AUC) for sublingual administration was slightly but not significantly smaller than after oral dosage (221 vs 270 h ng ml−1). Systemic availability of diphenhydramine after sublingual dimenhydrinate, measured by the ratio of oral AUC to intravenous AUC, was slightly less than after oral dimenhydrinate (0·58 vs 0·69, NS), and both were significantly less than 1·0. Thus sublingual and oral administration of dimenhydrinate result in comparable, but incomplete, systemic availability of diphenhydramine.
Intramuscular administration of atropine in the rat: Jet spray versus conventional needle injection
Authors: Lieske Claire N. , Lukey Brian J. , Hayward Isaac J. , Gepp Robin T. , Meyer Howard G. 
Published: October 2006

AbstractThe characteristics of atropine plasma levels after jet spray injection were compared to those after conventional needle injection (i.m.) in 12 male rats, six per group. Blood samples were sequentially collected from the tip of the tail over a 7h period. Injection of atropine sulfate (8.0mgkg−1) using the jet spray resulted in mean peak plasma levels of 650ngml−1 (95 per cent C.I. = 90) compared to 488ngmg−1 (95 percent C.I. = 64) using a conventional needle. Times to reach maximum concentration were 30min (95 per cent C.I. = 12) and 58min (95 per cent C.I. = 6) for the jet spray and needle, respectively. Histopathologic examination (5 days post‐injection) of target muscle showed that minimal fiber damage resulted from using the low pressure setting on the jet spray. The results suggest that the jet spray may offer a means of increasing the antidotal benefit over that achieved with conventional techniques using presently available therapeutic formulations for acetylcholinesterase poisoning.
Effects of dose and sex on the pharmacokinetics of piroxicam in the rat
Authors: Roskos Lorin K. , Boudinot F. Douglas 
Published: October 2006

AbstractThe effects of dose and sex on the pharmacokinetics of piroxicam were studied in the rat. Piroxicam was administered intravenously at doses of 0.50 and 5.0 mg kg−1 to male and female rats. Plasma drug concentrations were determined by a highly sensitive high‐performance liquid chromatographic technique. Non‐compartmental pharmacokinetic parameters were calculated by area/moment analysis. A prolonged terminal half‐life averaging 13.3 h in male rats and 40.8 h in female rats was observed. Dose had no effect on the disposition of piroxicam. The sex of the rat, however, had a marked effect on piroxicam pharmacokinetics, with mean total clearance differing three‐fold from 0.01841 h−1 kg−1 in male rats to 0.00622 1 h−1 kg−1 in female rats. The free fraction of piroxicam in serum was greater in male rats than in female rats owing to a higher association constant for piroxicam binding to female rat serum proteins. Free piroxicam clearance differed approximately two‐fold with mean values of 0.764 1 h−1 kg−1 and 0.418 1 h−1 kg−1 in male and female rats, respectively. Thus, protein binding partially explained the sex‐dependent disposition of piroxicam. However, sex‐dependent metabolism of the drug also appears to be a major determinant of sex‐related differences in piroxicam pharmacokinetics. Steady‐state volume of distribution was unaffected by sex. Half‐life and mean residence time were three‐fold greater in female rats owing to the three‐fold lower clearance value compared to male rats.