bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of controlled release formulations: Estimation of the duration of the zero‐order absorption and ascertainment of absorption kinetics
Authors: Macheras Panayotis 
Published: October 2006

AbstractA compartmental approach for estimating the duration of the zero‐order absorption was developed. For drugs obeying one‐compartment model disposition, the estimation is based on an explicit relationship while an iterative process is required for drugs represented by two‐compartment kinetics. A method based on a double graphical plot for ascertaining absorption kinetics for drugs exhibiting one‐compartment model disposition was also developed.
In vitro and in vivo assessment of the bioavailability of potassium from a potassium tartrate tablet
Authors: Whiting Susan J. , Gorecki Dennis K. J. , Jones Dennis 
Published: October 2006

AbstractThe bioavailability of potassium from orally administered potassium tartrate was evaluated in 20 normal subjects under metabolic balance conditions. Subjects were given 34 mmol potassium (5 tablets of Cal‐K®) as a divided dose on each of 2 consecutive days. Urinary excretion of potassium, as determined from 24‐h urinary collections on the 3 days preceding dosage totalled 192·6 ± 50·9 mmol (mean ± S.D., n = 20). It increased significantly (p < 0·05) to 258·7 ± 54·2 mmol for the 2 days of dosage and the following day. The difference of 66.1 mmol representing absorbed potassium was close to the 68 mmol potassium given and indicated a bioavailability of potassium in excess of 97 per cent; after correction for creatinine excretion, potassium recovery rose to 99·9 per cent. The dissolution characteristics of the Cal‐K® tablets were also determined. After dissolution in simulated gastric juice (pH 1·2), 84·4 ± 10·6 per cent (mean ± S.D., 6 experiments) was dissolved; after adjustment to pH 7·3, dissolved potassium increased to 91·3·8·5 per cent. No precipitation or residue formed as a result of the pH change. Both sets of results indicate that potassium from these potassium tartrate tablets is in a highly bioavailable form.
Pharmacokinetic studies of the nitroglycerin metabolites, 1,2‐ and 1,3‐ glyceryl dinitrates, in the rat
Authors: Lau David T.‐W. , Gumbleton Mark , Labisch Christoph , Benet Leslie Z. 
Published: October 2006

Abstract1,2‐ and 1,3‐glyceryl dinitrates (1,2‐GDN and 1,3‐GDN) are the primary metabolites of glyceryl trinitrate, a commonly used anti‐anginal agent. The goal of this study was to examine the pharmacokinetic properties of these metabolites in rats. Sprague‐Dawley rats were infused intravenously with 0·25 or 2·0 μgmin−1 of either 1,2‐ or 1,3‐GDN for 70 min, during which steady state blood concentrations were achieved. Post‐infusion blood samples were collected for 30 min. 1,2‐GDN was found to possess slightly higher clearance (32·3 vs 21·8 ml min−1 kg−1) and volume of distribution (695 vs 454 ml kg−1) than 1,3‐GDN; however, the two metabolites exhibited similar mean residence times (22·0 vs 21·8 min). Upon an 8‐fold increase in the infusion rate, the pharmacokinetic parameters were not significantly altered for either 1,2‐ or 1,3‐GDN. When each GDN was co‐infused with an 8‐fold higher dose of the other GDN, there were also no significant changes in the parameters.
Relative bioavailability of olsalazine from tablets and capsules: A drug targeted for local effect in the colon
Authors: Ryde M. , Huitfeldt B. , Pettersson R. 
Published: October 2006

AbstractThe aim of this investigation was to compare two formulations of the prodrug oisaiazine (OLZ) with regard to local bioavailability of 5‐aminosalicylic acid (5‐ASA) in the colon. Since 5‐ASA can not be measured directly in the colon, the bioavailability was evaluated by studying the plasma concentration and cumulative urinary excretion (Ae) of its main metabolite N‐acetyl‐5‐aminosalicylic acid (ac‐5‐ASA). The absorption of OLZ was also studied. A single dose of lg OLZ tablets and capsules was given to nine healthy fasting volunteers in two repeated two‐period cross‐over studies. Blood and urine samples were collected for 72 and 96h, respectively. AUC, Cmax and Ae data from both studies were combined for statistical analysis. Ninety per cent confidence limits for differences in mean AUC for ac‐5‐ASA (tablet‐capsule) compared to that of capsules were ‐0·31 per cent and 30·8 per cent. This indicates bioequivalence if a more relaxed criterion than the conventional ·20 per cent is applied, which is justified in this situation. The 90 per cent confidence limits for Cmax were ‐10·5 per cent and 36·9 per cent while for Ae the values were ‐20·5 per cent and 23·7 per cent. Within and between subject variability estimates for AUC of ac‐5‐ASA were 24 per cent and 46 per cent, respectively.
Metabolism of 14C‐2′,3′‐dideoxyinosine by the in situ perfused rat liver preparation
Authors: Tay Lee K. , Papp Eugene A. , Timoszyk Julita 
Published: October 2006

AbstractThe metabolism and biliary excretion of 14C‐dideoxyinosine (14C‐ddI) has been investigated using the in situ perfused rat liver (PRL) preparation. After 2h of perfusion through the liver, approximately 70–75 per cent of the total 14C‐radiolabel was recovered in the perfusion medium, less than 1 per cent was excreted in bile and 15–18 percent was retained in the liver. Hepatic clearance of ddI was 1·5 ± 0·1 ml min−1 and half‐life for the elimination of ddI from the medium was 22·9 ± 2·0 min (n = 3). Hepatic extraction was estimated to be 7·5 per cent. HPLC analysis of the effluent perfusate indicated that ddI was metabolized to hypoxanthine, xanthine, uric acid, and to a polar metabolite which was tentatively identified as allantoin. Approximately 60–65 per cent of the ddI dose was converted to allantoin after 2h of perfusion. Of the other three metabolites, uric acid levels increased to 20–30 per cent of the dose after 45 min and declined to about 5 per cent of the dose by the end of the perfusion period. Levels of hypoxanthine and xanthine were low and both compounds were not detected in the perfusate after 45 min post‐infusion. In bile, the major peak, which accounted for about 50 per cent of the 14C‐radiolabel co‐eluted with the putative metabolite, allantoin (0·4 per cent of the dose). Uric acid (0·06 per cent of the dose) was the only other metabolite detected in bile. These results suggest that biliary excretion is a minor pathway for the elimination of ddI. Furthermore, ddI is rapidly cleared and metabolized by the liver to hypoxanthine, xanthine, uric acid, and to allantoin.
Effects of phenobarbital and 3‐methylcholanthrene pretreatment on the pharmacokinetics and the pharmacodynamics of bumetanide in rats
Authors: Choi Young M. , Lee Sun H. , Jang Seong H. , Lee Myung G. 
Published: October 2006

AbstractThe effects of pretreatment with the enzyme inducers, phenobarbital (PB) and 3‐methyl‐cholanthrene (3‐MC), on the pharmacokinetic and pharmacodynamic parameters of bumetanide were examined in rats. The nonrenal clearance (19·3 vs 29·6 ml min−1 per kg) of bumetanide increased significantly in PB treated rats. This suggested that the nonrenal metabolism of bumetanide is increased by pretreatment with PB, which was supported by significantly increased amounts of bumetanide glucuronide and desbutyl bumetanide excreted in 8‐h urine, and reduced amounts of bumetanide remaining per gram of tissue after 30‐min incubation of 100 μg of bumetanide with the 9000 xg supernatant fraction of liver, stomach, and kidney tissue homogenates in PB treated rats. The contents of hepatic cytochrome P‐450 (1·29 vs 2·15 nmol mg−1 protein) and the weights of liver and stomach increased significantly in PB treated rats, suggesting that the metabolizing enzymes for bumetanide are induced by pretreatment with PB. The 8‐h urine output per 100g body weight was not significantly different by pretreatment with PB although the amounts of bumetanide excreted in 8‐h urine increased significantly in PB treated rats. It could be explained by the fact that the dose of bumetanide used results in urinary concentrations at the plateau of the concentration–effect relationship. Therefore, the alteration in the urinary excretion rate of bumetanide by pretreatment with PB would not alter the diuretic effect. In 3‐MC treated rats, pharmacokinetic and pharmacodynamic parameters were not significantly different and it suggested that the metabolizing enzymes for bumetanide are not induced by pretreatment with 3‐MC although the contents of hepatic cytochrome P‐450 and the weights of liver and stomach increased significantly by pretreatment with 3‐MC.
Comparison of in vitro and in vivo release characteristics of acetaminophen from gradient matrix systems
Authors: Van Bommel Elvira M. G. , Raghoebar Maikel , Tukker Josef J. 
Published: October 2006

AbstractAn effort was made to correlate the in vivo and in vitro release data of acetaminophen from two formulations of a recently developed controlled‐release system, the Gradient Matrix System (GMS‐1 and GMS‐2). The in vivo release curves, obtained by deconvolution of the plasma concentration time plots, showed a small inter‐subject variability. GMS‐1 with fastest in vitro release also showed fastest in vivo release. A good relationship was only found after time‐scaling of the release data.
Pharmacokinetic comparison of a combination tablet of enalapril and hydrochlorothiazide with enalapril and hydrochlorothiazide tablets administered together and separately
Authors: Howes L. G. , Conway E. L. , Phillips P. A. , Broadbear J. , Drummer O. H. , Louis W. J. 
Published: October 2006

AbstractEnalapril and hydrochlorothiazide (HCT) are established single agent treatments for mild hypertension and cardiac failure and are a potent combination in more severe or resistant cases. We have compared the pharmacokinetics of enalaprilat (the active metabolite of enalapril) and HCT in a four‐way comparison of a combination tablet of enalapril (10mg)/HCT (25 mg) with a single dose of an enalapril tablet (10 mg), a single dose of a HCT tablet (25 mg) and simultaneous administration of separate tablets of enalapril (10 mg) and HCT (25 mg) in normotensive volunteers (n = 12, 21–26 years). Each subject received all four treatments and the study was conducted as a randomized, latin square, open design with at least 1 week washout between studies. Overall, HCT was bioequivalent under all conditions and enalaprilat was bioequivalent when given in combination with HCT either as one tablet or as two separate tablets. However, when given with HCT, the mean AUC and Cmax of enalaprilat were reduced up to 20 per cent compared with enalapril administered alone. This is unlikely to be of clinical significance as the differences did not reach statistical significance and the total enalaprilat excreted in the urine over 96 h was similar after all treatments.
Pharmacokinetics of azithromycin after single oral dosing of experimental animals
Authors: Davila D. , Kolačny‐babić Lidija , Plavšić F. 
Published: October 2006

AbstractAzithromycin, a macrolide antibiotic with an enhanced antimicrobial spectrum, was found to have a longer half‐life than erythromycin, with marked tissue penetration. The pharmacokinetics of azithromycin after oral administration were compared with those of erythromycin in rats (200 mg kg−1) and rabbits (80 mg kg−1). Concentrations of azithromycin in liver, lung, kidney, ileum, and brain were higher than serum concentrations. The slow decline in tissue concentrations was evident from the biphasic elimination profile. Thus, advantageous pharmacokinetic properties and the broader antimicrobial spectrum of azithromycin relative to erythromycin appear to further support its therapeutic potential.
Dermal absorption of niclosamide in rats and minipigs
Authors: Brennan Patricia , Johnson Debra , Rider Susan , Cone Norm , Goldman Marvin , Buckpitt Alan , Chung Ho 
Published: October 2006

AbstractThe dermal absorption of niclosamide, a drug shown to prevent Schistosomiasis by blocking the dermal penetration of cercariae, has been examined in Sinclair minipigs and rats. Radioactivity in the urine and feces collected daily for 7 days after application of 14C‐niclosamide accounted for less than 2 per cent and 10 per cent of the labelled compound applied to pig and rat skin, respectively. Approximately 20 per cent of the radioactivity from the dose solution was recovered on the skin excised from the area of application in both minipigs and rats. No radioactivity was detected in organs removed from the pig 7 days after application of radiolabelled drug while less than 6 per cent of the dose could be accounted for in the rat organs/carcass. Radioactivity in swine blood, removed 0·5, 1, 2, 4 and at 24 h intervals after dosing, was at or below three times background in all of the samples. Total recovery of the applied radioactivity was 78 per cent in pigs and 57 per cent in rats. These studies indicate that niclosamide is very poorly absorbed after dermal application. The results are consistent with earlier comparative studies showing that dermal penetration of xenobiotics in rats is generally higher than in swine.
Factors influencing the protein binding of vancomycin
Authors: Shin Wan G. , Lee Myung G. , Lee Min H. , Kim Nak D. 
Published: October 2006

AbstractVarious factors influencing the protein binding of vancomycin were examined using equilibrium dialysis method. Four per cent human serum albumin (HSA) and/or 0·08 per cent alpha‐1‐acid glycoprotein (AAG), dissolved in isotonic phosphate buffer, were dialyzed against isotonic phosphate buffer of pH 7·4 using Spectrapor 2 membrane. The protein binding of vancomycin to 0·08 per cent AAG was dependent on vancomycin concentrations; the values ranged from 21·1 per cent at the vancomycin concentration of 20 μg ml−1 to 5·30 per cent at 2400 μg ml−1. However, binding to 4 per cent HSA was relatively constant, 8·79 ± 2·43 per cent over a vancomycin concentration range of 20–2400 μg ml−1. The values to 4 per cent HSA alone and 0·08 per cent AAG alone did not predict the greater binding of vancomycin in the presence of both proteins, especially at higher concentrations of vancomycin; the values to 4 per cent HSA with 0·08 per cent AAG were constant, 26·3 ± 3·74 per cent, at the vancomycin concentration range of 20–2400 μg ml−1. This suggested an interaction between the proteins, which resulted in enhanced binding of vancomycin. The protein binding of vancomycin to 4 per cent HSA with 0·08 per cent AAG was not influenced by the different incubation temperatures (4°, 22°, and 37°), quantities of heparin (up to 40 units ml−1) or AAG (up to 0·16 per cent), or buffers (isotonic phosphate buffer of pH 7·4, phosphate buffer of pH 7·4 and 0·9 per cent NaCl solution) at the vancomycin concentration of 80 μg ml−1. Vancomycin was found to be stable in human serum albumin or in isotonic phosphate buffer of pH 7·4.
Effect of dehydration on the disposition kinetics of erythromycin in rabbits
Authors: Ahmad M. , Niazi S. K. , Ahmad T. , Muzaffar N. A. , Nawaz M. 
Published: October 2006

AbstractThe effect of water deprivation on the physiologic, biochemical, and disposition parameters of erythromycin was investigated in rabbits. The packed cell volume, plasma glucose, and total lipid concentration increased significantly in dehydration. The pharmacokinetic parameters of erythromycin after intravenous administration also changed, suggesting a need for monitoring toxicity of erythromycin in the water‐deprived population.
Pharmacokinetics of the antidepressant levoprotiline after intravenous and peroral administration in healthy volunteers
Authors: Kaiser G. , Ackermann R. , Dieterle W. , Reimann I. W. , Bieck P. R. 
Published: October 2006

AbstractTo investigate the pharmacokinetics and the disposition of levoprotiline after i.v. and p.o. administration and to assess the absolute bioavailability, 12 healthy volunteers (11 women, 1 man) were given a 10 min i.v. infusion of 15 mg and a p.o. dose of 75 mg in a two‐way crossover study. Blood and urine samples were collected after each dose. Unchanged levoprotiline and the sum of unchanged and glucuronidated levoprotiline (=total levoprotiline) were determined by a specific gas chromatographic‐mass spectrometric method.Intravenous levoprotiline was rapidly and extensively distributed into extravascular sites of the body; the steady‐state volume of distribution was 18·81 kg−1. The elimination of levoprotiline from blood was independent of the dosing route, the half‐life being 18·8h. Only 1·8 and 0·6 per cent of the i.v. and p.o. dose, respectively, were excreted unchanged in the urine, whereas 57 per cent of each dose were renally excreted as total levoprotiline.The absolute bioavailability of p.o. levoprotiline was 40 per cent. About 60 per cent of the dose was subject to a first‐pass effect in the liver. The systemic blood clearance of levoprotiline, determined after i.v. dosing, was 885 ml min−1, the renal blood clearance after i.v. and p.o. dosing was only 16·0 and 14·2 ml min−1, respectively. Presystemic and systemic clearance of levoprotiline occurred predominantly by direct glucuronidation.
Prediction of netilmicin disposition in neonates
Authors: Darwish M. , Batayneh M. , Jenkins J. , Scott M. , Collier P. S. , McElnay J. C. 
Published: October 2006

AbstractMultiple regression analyses of data from 33 neonates who received netilmicin therapy showed that concurrent treatment with other drugs (Drg), creatinine clearance (CLcr), gestational age (GA), and an apgar score of less than 6 at 1 min (Agl') were significant determinants of netilmicin clearance. Apparent volume of distribution was significantly affected by postnatal age (PNA), gender, the presence of ascites and/or oedema (A/O), and whether or not the neonate was small for gestational age (SGA). The following formulae were obtained: magnified image.The regression formulae were shown to predict netilmicin plasma concentrations with good precision and a non‐significant bias in a further 15 neonates studied prospectively.
Pharmacokinetics of nitroglycerin and its metabolites after administration of sustained‐release tablets
Authors: Kwon Hae‐Ryun , Green Preston , Curry Stephen H. 
Published: October 2006

AbstractNitroglycerin was administered to eight healthy volunteers in the form of sublingual tablets, oral sustained‐release tablets, and an oral solution. Blood samples were collected for measurement of nitroglycerin and its two isomeric glyceryl dinitrate metabolites. Blood pressure and pulse rate were monitored; subjective evaluations of headache, dizziness, facial flushing, skin irritation, and gastrointestinal upset were made. Nitroglycerin itself was virtually undetectable after the solution and tablet preparations; the metabolites were consistently detectable from a few minutes after dosing to 24h later. Mean total (nitroglycerin plus metabolite) concentrations were comparable in the 15 min following sublingual administration, and the 8h following tablet administration. The relative bioavailability of the tablets in comparison with the oral solution was 70 per cent based on metabolite concentrations. Nitroglycerin sustained‐release tablets appear to exert their beneficial effects in the prolonged prophylaxis of angina through active metabolites.
In vitro reduction of rhein anthraquinone to rhein anthrone by rat cecal microflora and some intestinal bacterial strains
Authors: de Witte P. , van Hoestenberghe A. , Eyssen H. 
Published: October 2006

AbstractAfter in vitro incubation of cecal content from CVL or gnotobiotic rats with rhein anthraquinone (1 mg g−1) for 18 h at 37°, the anthraquinone was converted to rhein anthrone for 23·5 (SD ± 3·4) per cent and 19·4 (±4·7) per cent, respectively. Liquid cultures of some strictly anaerobic fecal bacteria of man and mouse incubated with rhein anthraquinone (62·5 μg ml−1) for 48 h at 37°, revealed only smail amounts of reduced substance. Although the underlying mechanisms of the differences in both conditions remain unclear, the experimental data accentuate the need for using cecal content when exploring the in vitro metabolism of anthranoids by the intestinal microflora. The conversion was chemically proven by derivatization of the anthrone with 4‐nitroso‐N‐N‐dimethylaniline in pyridine, followed by hydrolysis and identification of the released anthranoid by mass spectrometry. The in vitro reduction capacity of the cecal content of CVL rats was drastically decreased by oral administration to rats of different combinations of neomycin sulfate, metronidazole, bacitracin and Na‐penicillin G. In these cases the conversion ranked between 0·2 per cent and 5·2 per cent the first day after administration. It is concluded that rhein anthraquinone in cecal content is reduced to the highly reactive and labile rhein anthrone, which accounts for the in vivo disappearance of dihydroxy‐anthranoid equivalents in routine analysis after oral administration of anthraquinones to experimental animals.
Pharmacokinetics of ketotiffn after oral administration to healthy male subjects
Authors: Grahnén A. , Lönnebo A. , Beck O. , Eckernäs S‐Å , Dahlström B. , Lindström B. 
Published: October 2006

AbstractThe pharmacokinetics of 2 mg ketotifen from four different oral dosage forms were examined in two randomized, balanced cross‐over studies. Forty healthy male subjects participated. Each of 20 subjects received two capsule formulations and each of the other 20 subjects received two syrup formulations. Ketotifen concentrations in plasma were determined by a modified GC—MS method. The limit of quantitation was 40 pg ml−1. Inter‐day precision and accuracy calculated from quality control samples were 16·3 per cent (−1·9 per cent), 19·8 per cent (+4·5 per cent) and 23·6 per cent (+ 5·9 per cent) at plasma concentration levels of 86 (n = 18), 215 (n = 19) and 343 (n = 18) pg ml−1, respectively. Ketotifen was rapidly absorbed from all dosage forms reaching Cmax in the order of 400 pg ml−1 after the syrup formulations and 300 pg ml−1 after the capsule formulations within 2 to 4 h. The syrup formulations showed a significantly more rapid rate of absorption as assessed by Tmax. No significant differences in extent of absorption between dosage forms were observed. The terminal elimination half‐life of ketotifen varied between subjects from 7 to 27 hours with a mean of about 12 h. The minor pharmacokinetic difference between dosage forms observed in this study is unlikely to be of clinical significance.
Absorption and disposition of fluvastatin, an inhibitor of HMG‐CoA reductase, in the rabbit
Authors: Tse F. L. S. , Labbadia D. 
Published: October 2006

AbstractThe absorption and disposition of fluvastatin have been studied in the female rabbit. In naive rabbits receiving a single oral dose (1 mg kg−1) of [3H] fluvastatin, absorption was rapid and amounted to c. 90 per cent compared with an intravenous reference dose. The drug was subject to considerable first‐pass effect, its absolute bioavailability being 46 per cent. The steady‐state volume of distribution of fluvastatin was 0·29±0·04 1 kg−1 while the total body clearance was 0·33±0·05 1 h−1 kg−1. The administered radioactivity was excreted predominantly in feces, with the renal pathway accounting for 28±4 per cent of the oral dose and 32±3 per cent of the intravenous dose. In pregnant rabbits on a multiple oral dosing regimen, 1 mg kg−1 day−1 beginning day 6 post‐conception (p.c.), steady‐state concentrations in maternal blood and tissues were achieved within 5 days. The concentrations in the reproductive organs were c. 25–50 per cent of that in maternal blood while those in the kidneys and liver were considerably higher. In contrast, radioactivity levels in the fetuses and amniotic fluid decreased significantly during repeated drug administration. The fetus: placenta and amniotic fluid: placenta concentration ratios declined from 0·92 and 0·97, respectively, on day 10 p.c. to 0·10 and 0·04, respectively, on day 18 p.c., indicating a limited transfer of fluvastatin and/or its metabolite(s) across the placenta at the later stage of pregnancy. After cessation of dosing, radioactivity levels in all tissues and fluids showed a progressive and nearly parallel, decline, suggesting no tissue retention of the drug.