bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic and pharmacodynamic studies in man with an antianginal agent ‘Visacor’
Authors: Cockshott Ian D. , McAinsh James , Norris Stephanie 
Published: October 2006

AbstractThis randomized, double‐blind, crossover study in 10 healthy male volunteers compared four single oral doses of ICI 141,292 (‘Visacor’), i.e. 50, 100, 200, and 300 mg, with placebo. Venous blood samples were collected pre‐dose and at various times after dosing and the concentrations of ICI 141,292 in the plasma were determined by radioimmunoassay. A standardized 4‐min bicycle exercise test was also performed and before this the resting haemodynamic parameters were assessed.Peak plasma concentrations of ICI 141,292 and the area under the plasma concentration–time curve increased disproportionately with dose such that after scaling to a dose of 200 mg there remained a significant linear trend with dose. The time to peak plasma concentration displayed an increasing trend with dose and, once again, the linear component of this trend was statistically significant. The mean heart rates during exercise were all significantly reduced compared to placebo for 24 h by each of the doses (range 7·8 to 17·4 beats min−1 at 24 h, p <0·01). The increase in heart rate during exercise was inversely related to the logarithm of the ICI 141,292 plasma concentration with higher plasma concentrations being associated with lower heart rate increases. The mean supine resting heart rates were slightly but significantly reduced at 2 and 6 h after dosing by each treatment and by the 300 mg dose at 24 h. Each of the doses of ICI 141,292 was well tolerated.
Pharmacokinetic aspects of the sublingual administration of vincamine
Authors: Aiache J‐M. , Delatte M‐C. , Leblanc P‐P. , Kantelip J‐P. , Steimer J‐L. 
Published: October 2006

AbstractThe sublingual absorption of vincamine used as tracer occurs in two successive absorption steps: true sublingual absorption and absorption in the gastrointestinal tract of the drug dissolved in the saliva and not absorbed through the buccal mucosa. This is confirmed by a pharmacokinetic study and simulation. These two successive absorptions can explain the increase in the amounts of drug absorbed.
Analysis and stereoselective metabolism after separate oral doses of tocainide enantiomers to healthy volunteers
Authors: Hoffmann Kurt‐Jürgen , Renberg Lars , Gyllenhaal Olle 
Published: October 2006

AbstractThe potential of stereoselective metabolism of tocainide was studied in six healthy volunteers after separate oral administration of the pure enantiomers in solution. A method was developed to convert the N‐carbamoylglucuronide of tocainide in plasma and urine by base treatment to a hydantoin derivative which after extraction and silylation was analysed by selected ion monitoring using a deuterated internal standard. Analytical problems concerning side‐reactions during derivatization of the conjugate are discussed.The peak plasma levels of the enantiomers, observed at ≦2 h after dosing, were similar but plasma clearances and terminal half‐lives were different after oral administration of (R)‐tocainide (195.5 ± 20.1 ml min−1 and 9.7 ± 0.8 h) and (S)‐tocainide (110.2 ± 10.5 ml min−1 and 14.5 ± 1.7 h). Over 0–96 h the averaged urinary recovery of (R)‐tocainide was 36 per cent and of (S)‐tocainide 50 per cent. Stereoselective metabolism was a likely mechanism for the observed differences as the urinary recovery of the conjugate formed from (R)‐tocainide differed substantially from that of (S)‐tocainide (45 vs 1.2 per cent of given dose). Plasma t1/2 of the (R)‐ and (S)‐conjugate were 9.9 and 18.7 h, respectively, indicating formation rate limited kinetics of the metabolite. The renal clearances of the conjugates were not significantly different (131 vs 97 ml min−1).
Effects of inducers and inhibitors of mixed‐function oxidases on the biliary excretion of pentacaine metabolites
Authors: Kukan M. , Bezek Š. , Ščasnár V. , Ďurišová M. , Trnovec T. 
Published: October 2006

AbstractThe biliary excretion of 3H‐pentacaine and its metabolites was studied in rats pretreated with an inducer or inhibitor of mixed‐function oxidases. Over one‐fourth (25·8 per cent) of a 2 mg kg−1 intraportal dose of 3H‐pentacaine was excreted in bile in urethaneanaesthetized control rats within 3 h. The radioactivity appeared in the form of the parent drug, basic metabolites, and metabolite conjugates, 3·1, 86·5, and 10·4 per cent of the total radioactivity excreted, respectively. Pretreatment of rats with phenobarbital enhanced only slightly the biliary excretion of basic metabolites, and pretreatment with 3‐methylcholanthrene had no effect. Phenobarbital also increased the initial rate of excretion of conjugates, but this effect was not sustained. 3‐Methylcholanthrene had a tendency to impair excretion of conjugates by bile. Pretreatment of rats with SKF 525‐A decreased the biliary excretion of both basic metabolites and conjugates while cimetidine did not alter significantly the biliary excretion of pentacaine metabolites. These results suggest that the canalicular transport of metabolites may be the most important factor in controlling pentacaine metabolite excretion in bile.
Kinetics of biliary elimination of pentacaine in rats
Authors: Bezek Š. , Ščasnár V. , Kukan M. , Trnovec T. 
Published: October 2006

AbstractPentacaine, a local anaesthetic of the carbanilate type, administered intravenously as 3H‐pentacaine, 2mg kg−1 to rats, was eliminated in the bile mainly in the form of metabolites (20·5 ± 1·5 per cent of the dose) and as parent drug (0·1 per cent of the dose) within 3 days. In control rats 32·2 ± 2·5 and 37·8 ± 2·5 per cent of 3H‐dose, representing pentacaine metabolites, were excreted in the urine and faeces, respectively. In bile‐ductucannulated rats 35·7 ± 6·8, 11·2 ± 3·4, and 20·5 ± 1·5 percent of 3H‐dose were excreted in the urine, faeces, and bile, respectively. The high 3H recovered in faeces in animals with diverted bile flow indicated passage of pentacaine metabolites through the intestinal wall. The excretion of pentacaine and its metabolites in bile was an active process, since the ratio bile/plasma concentration rapidly attained values approaching 10. In rats with ligated ureters the biliary elimination of pentacaine and its metabolites was enhanced, compensating for impaired urinary excretion. This was accompanied by increased plasma and brain levels of 3H compared with untreated controls.
Disposition of fluvastatin, an inhibitor of HMG‐CoA reductase, in mouse, rat, dog, and monkey
Authors: Tse F. L. S. , Smith H. T. , Ballard F. H. , Nicoletti J. 
Published: October 2006

AbstractThe physiological disposition of fluvastatin, a potent inhibitor of hydroxymethylglutaryl‐CoA reductase and thus cholesterol synthesis, has been studied in the mouse, rat, dog, and monkey using 14C or 3H‐labeled drug. Oral doses of fluvastatin were absorbed at a moderate to rapid rate. The extent of absorption was dose‐independent and was essentially complete in all four species studied. However, the drug was subject to extensive presystemic hepatic extraction followed by direct excretion via the bile, thus minimizing the systemic burden and yielding high liver/peripheral tissue concentration gradients for fluvastatin and its metabolites. Only at high doses far exceeding the intended human daily dose of ca 0·6 mg kg−1 did fluvastatin bioavailability approach unity, apparently due to saturation of the first‐pass effect. Dose‐normalized blood levels of fluvastatin and total radioactivity were higher in the dog than in the other species, suggesting a smaller distribution volume in the former. Fluvastatin was partially metabolized before excretion, the extent of metabolism being smallest in the dog and greatest in the mouse. The half‐life of intact fluvastatin ranged from 1–2 h in the monkey to 4–7 h in the dog. Regardless of the dose or dose route, the administered radioactivity was recovered predominantly in feces, with the renal route accounting for less than 8 per cent of the dose. No tissue retention of radioactivity was observed, and material balance was essentially achieved within 96 h after dosing.
Pharmacokinetics of promazine: I disposition in patients with acute viral hepatitis B
Authors: Hu Oliver Y.‐P. , Tang Hung‐Shang , Sheeng Tuzen‐Yan , Chen Sung‐Chao , Lee San‐Kan , Chung Ping‐Hong 
Published: October 2006

AbstractConcentrations of promazine in plasma, plasma water, red blood cells, and urine were measured after oral administration of the drug to six patients during and after apparent recovery from the acute phase of viral hepatitis B. None of the promazine pharmacokinetic parameters were significantly different during and after the acute phase; these parameters included clearance, free drug clearance, metabolic clearance, volume of distribution, distribution and elimination half‐life values, plasma protein binding, and per cent excreted in the urine. During the acute period of the illness, SGOP, SGPT, alkaline phosphatase, and total bilirubin were increased in all patients; they returned to within or near the upper limits or normal after recovery. Despite the unchanged promazine disposition, four out of six patients had more severe promazine side‐effects, such as sedation, postural hypotension, and dizziness during the acute phase of the illness. This study suggests that promazine disposition was not significantly altered as a consequence of viral hepatitis. However, the pharmoacodynamic effects of promazine were changed significantly. Care must be taken with patients who are taking promazine during the acute phase of viral hepatitis B.
Pharmacokinetics of pafenolol after IV and oral administration of three separate doses of different strength to man
Authors: Regårdh C. G. , Heggelund A. , Kylberg‐Hanssen K. , Lundborg P. 
Published: October 2006

AbstractThe pharmacokinetics of pafenolol were evaluated in 12 healthy subjects after administration of three single IV doses (5, 10, and 20mg) and three oral single doses (25, 50, and 100mg). The drug was discontinuously absorbed. A first peak was observed 0·5 to 1·5h after dosing and a second higher maximum concentration was noted 3 to 5h after the administration in the majority of the experiments. The mean systemic availability increased from 27 ± 5 per cent for the oral 25 mg dose to 46 ± 5 per cent for the 100mg dose, i.e., an increase of about 70 per cent (p < 0·05). The half‐life of distribution varied between 5 and 6min and the apparent volume of distribution (Vz) was about 1·11 kg−1. The distribution was linear in the IV dose range studied. Total body clearance was about 300ml min−1. About 50 per cent of the systemically available dose was excreted unchanged via the kidneys. Total body clearance decreased by about 13 per cent (p < 0·05) by increasing the dose from 5 to 20mg IV possibly because of reduced renal elimination. Mean terminal t1/2 of the IV dose was ∽ 3·5h. The corresponding t1/2 of the oral dose was ∽ 6h indicating absorption rate‐limited kinetics of the oral dose.
Regional pharmacokinetics I. physiological and physicochemical basis
Authors: Upton Richard N. 
Published: October 2006

AbstractSystemic pharmacokinetics is the study of the time‐course of drug concentrations in ‘systemic’ blood sampled from either an arterial, central venous or peripheral venous blood vessel. It is generally not suitable for studying the pharmacokinetics of drugs in individual organs of the body, when the blood concentrations of a drug are changing rapidly, or when the physiological or pathophysiological status of a patient is unstable. Regional pharmacokinetics addresses some of these limitations and is based on the study of the factors influencing drug concentrations in specific regions (tissues, organs) of the body due to the movement of drug from blood into and out of the region (drug ‘uptake’ and ‘elution’, respectively). It provides a vital link between systemic pharmacokinetics and molecular pharmacology. The physiological basis of regional pharmacokinetics is a function of the interactions of the drug between the cells and proteins in blood, the blood flow supplying a region, the structure of the capillaries of the region and the types of specific and non‐specific binding within the region. The physicochemical basis of regional pharmacokinetics is a function of the factors influencing the rate and extent of diffusion of a drug through aqueous and lipid mediums, such as molecular weight, ionization, charge, and lipophilicity.
Pharmacokinetic modelling of the plasma concentration‐time profile of the vitamin retinyl palmitate following intramuscular administration
Authors: Hartmann D. , Gysel D. , Dubach U. C. , Forgo I. 
Published: October 2006

AbstractSeven healthy male volunteers (21–24 y) received by the ventro‐gluteal route a single dose of 100 000 I.U. of the vitamin retinyl palmitate (RP) in a water‐miscible preparation (W) and 5 weeks later the same dose in an oily solution (S). After administration of W median (range) peak plasma concentrations of 5.6(4.4–8.7). 103 μg 1‐−1 were reached after 12 h and high levels persisted for another 50 h. At 144 h levels were still, by a factor 3, higher than baseline. Plasma levels of RP after S remained close to baseline (20–50 μg.1−1) suggesting negligibly low bioavailability. The plasma level profile of RP after W could well be described by use of a one‐compartment model with Weibull‐type absorption and Michaelis‐Menten elimination. The median (range) absolute bioavailability (estimates of lower limits) was 42 (32–52) per cent.
Effect of food on the bioavailability of adinazolam from a sustained release formulation: Effect of meal timing and lack of dose dumping
Authors: Fleishaker J. C. , Phillips J. P. , Lau H. S. H. 
Published: October 2006

AbstractFood effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets. 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N‐desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state: no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0·5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.
Pharmacokinetics of dibenzylamine administered in a sustained drug delivery system with cefazolin
Authors: Calvo M. B. , Pedraz J. L. , Dominguez‐Gil A. 
Published: October 2006

AbstractThe pharmacokinetics of dibenzylamine administered in a sustained drug delivery system with cefazolin was studied after i.m. administration of a dose of 1250 mg to healthy volunteers. The serum and urine levels of dibenzylamine were determined by a GLC technique using a specific nitrogen‐phosphorus detector. Characterization of the kinetic parameters was performed by applying compartmental and non‐compartmental analysis.Dibenzylamine was found to reach concentrations close to 300ng ml−1 approximately 5h after administration. The elimination constant had a value of 0·832 ± 0·821 h−1 (mean ± S.D.), which is higher than the release constant of the derivative (0·109 ± 0·072 h−1) (mean ± S.D.). These results show that release of dibenzylamine may be considered the limiting kinetic process, which governs the elimination of the product from the organism. Only a small amount of dibenzylamine is excreted in urine unchanged 3·43 ± 3·28 per cent (mean ± S.D.).Using the pharmacokinetic parameters calculated for dibenzylamine, a prediction has been made of the concentrations reached in a multiple dosage regimen after administration of a dose of 1250 mg every 24h. The accumulation factor was 1·09.
Regional pharmacokinetics III. Modelling methods
Authors: Upton Richard N. , Runciman William B. , Mather Laurence E. 
Published: October 2006

AbstractRegional pharmacokinetics is the study of drug concentrations in specific regions of the body due to drug uptake and elution. Mathematical methods of interpreting regional pharmacokinetic data can vary greatly in their complexity depending on their intended use (i.e. to describe or predict), but must reinforce rather than replace experimental pharmacokinetics. ‘Black box’ analysis provides and empirical method for the study of complex pharmacokinetic systems using either statistical moment or linear systems analysis. However, these methods are only applicable to linear and time‐invariant systems, and ignore the large body of information concerning the physiological and physicochemical basis of regional pharmacokinetics. Clearance concepts are suitable for describing linear drug uptake processes, but mass balance principles have wider applications in describing the rate and extent of both drug uptake and elution. Compartmental models of a region can vary from single compartment descriptions based on the concept of venous equilibrium to complex multi‐compartmental models of the intra‐vascular, interstitial, and intracellular spaces, in which drug transport between compartments is a function of drug binding and ionization. Ultimately, as more regional pharmacokinetic information is obtained, more complex three dimensional models may be necessary such as those used to describe the uptake of oxygen from capillaries.
Effect of H2‐receptor antagonists on the pharmacokinetics of 5‐fluorouracil in the rat and monkey
Authors: Dilloway Mark R. , Lant F. 
Published: October 2006

AbstractThe effect of short term (7 days) and long term (28 days) pretreatment with the imidazole H2‐receptor antagonist, cimetidine (CMT), on the pharmacokinetics of 5‐fluorouracil (5‐FUra) has been studied in the rat and cynomolgus monkey. Short‐term pretreatment of rats with CMT significantly increased t1/2,z by 29 per cent and AUC by 40 per cent: total body clearance was decreased by 30 per cent. Long‐term pretreatment exaggerated these effects. By contrast, short‐ and long‐term pretreatment with the furan H2‐receptor antagonist, ranitidine, caused no significant effect on 5‐FUra kinetics. In the monkey, 7 days pretreatment with CMT increased t1/2,z by 32 per cent leaving other 5‐FUra kinetic parameters unchanged; 28 days pretreatment increased both t1/2,z by 41 per cent and AUC by 100 per cent with a decrease in total body clearance of 5‐FUra of 48 per cent. CMT, but not RNT, inhibited cytosolic dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5‐FUra catabolism. It is proposed that the observed effects of CMT on 5‐FUra kinetics are the result of inhibition of DPD. This interaction has the potential for increasing systemic drug toxicity and it is therefore advisable that where H2‐receptor blockade is administered concurrently with 5‐FUra that a non‐imidazole based H2‐receptor antagonist such as RNT should be substituted for CMT.
A high‐performance liquid chromatographic method for the determination of stobadin pharmacokinetics in serum
Authors: Šoltés Ladislav , Kállay Zoltán , Bezek Štefan , Fedelesǒvá Viera 
Published: October 2006

AbstractA high‐performance liquid chromatographic method was developed to determine stobadin pharmacokinetics in dog and man. The relative bioavailability of stobadin dipalmitate compared with dihydrochloride was 46·4 per cent in dog. In man peak serum concentrations ranged from 12 to 289ng ml−1 after a single oral dose of stobadin dipalmitate (0·79 to 2·5mg kg−1).
The influence of diuretics on the excretion and metabolism of doping agents: Part VI. Pseudoephedrine
Authors: Delbeke F. T. , Debackere M. 
Published: October 2006

AbstractA capillary gas chromatographic method with nitrogen specific detection is presented for measuring pseudoephedrine and its major metabolite norpseudoephedrine in urine after derivatization with trifluoroacetic anhydride. After the oral intake of 49·2 mg pseudoephedrine (ACTIFED®) the active substance is nearly quantitatively excreted in urine over a 48 hr period. From 1 to 7 per cent is metabolized to norpseudoephedrine. The intake of acetazolamide results in a suppression of the pseudoephedrine concentration for at least 12h. The diuretic effect after the intake of 1·51 mineral water could be compared with the effect obtained with 1 mg bumetanide and results in a decrease in pseudoephedrine concentration by a factor 4 for several hours.
Etretinate absorption in the in situ perfused intestinal lumen: Preliminary studies in the rat
Authors: Zimmerman Cheryl L. , Johnson Kenneth E. 
Published: October 2006

AbstractThe absorption characteristics of etretinate were examined in the Sprague‐Dawley rat with the use of the in situ intestinal lumen perfusion model. Intestinal segments of 15–50cm were cannulated and perfused with etretinate solutions of 178–1405 μgml−1 in a single‐pass manner at flow rates of 0·15–0·96 ml min−1. The intestinal effluent was collected and analyzed by HPLC for etretinate, as was blood that was drawn from the jugular vein. Despite its lipophilic nature, etretinate does not appear to be well absorbed from the rat intestine; the maximum fraction disappearing from the intestinal lumen was approximately 0·35. The absorption of etretinate appeared to be controlled by the aqueous diffusion layer. There was no evidence that the uptake of etretinate by the gastrointestinal membrane involved an active transport system.
Drug redistribution and mean transit time concepts for nonlinear pharmacokinetic systems
Authors: Cheng Haiyung , Jusko William J. 
Published: October 2006

AbstractEquations for the mean number of cycles through the peripheral system (R) and the mean transit time through the central compartment (MTTc) are derived for intravenous drugs with linear distribution and linear or nonlinear central elimination. This R is a function of distribution clearance (CLD), dose, and area under the plasma concentration–time curve (AUC). The MTTc is a function of the central volume of distribution, CLD, dose, and AUC. The application of the proposed calculations of R and MTTc was illustrated by computer simulations.
Pharmacokinetics of intravenous diltiazem and five of its metabolites in patients with chronic renal failure and in healthy volunteers
Authors: Tawashi Maha , Marc‐aurèle Julien , Bichet Daniel , Spénard Jean , Larivière Lyne , Plante Daniel , Caillé Gilles 
Published: October 2006

AbstractThe pharmacokinetics of diltiazem were studied in seven patients with chronic renal failure (CRF) not requiring dialysis and in three healthy volunteers after a rapid i.v. infusion of 20mg. Mean plasma concentrations at the end of infusion were 3·15 times higher in patients with CRF than in healthy volunteers. From 0·5 to 12h post‐infusion, the difference remained between 25 per cent and 73 per cent. Mean AUC0–∞ was statistically greater in patients than in volunteers while mean V area, CLtot, and CLren were statistically lower. The t1/2α and tβ values were not significantly (p > 0·05) different between patients and volunteers. Renal excretion was statistically more important in volunteers (6·6 per cent of the dose) than in patients (1·2 per cent of the dose). We therefore conclude that CRF does not influence t1/2β of diltiazem but it interferes with the extent and possibly the rate of its extravascular distribution. That could result in transient high plasma concentrations after rapid i.v. infusion.