bluuebunny/crossref_metadata_2025_split huggingface dataset:
Significance of ratios of different volumes of distribution in pharmacokinetics
Authors: Wagner John G. 
Published: October 2006

AbstractMulticompartmental pharmacokinetics involves the four volumes: Vc = volume of the central compartment; Vss = volume of distribution steady‐state; Vβ = volume of distribution beta; and Vext = the extrapolated volume of distribution. The ratio Vc/Vext is indicative of the degree of multicompartmental character of a set of data. The quantity (Vext/Vβ)−1 is the fractional error in the total clearance when one assumes a monoexponential rather than a polyexponential equation for disposition of a drug. The ratio Vss/Vβ indicates how well the one‐compartment body model predicts average amounts of drug in the body when a multicompartmental model is actually operative. The quantity (Vss/Vc)− 1 is equal to either k12/k21 or k12/k21 + k13/k31 of the two‐ and three‐compartmental mammillary models. Examples from the literature are reported and discussed.
Pharmacokinetics, acetylation‐deacetylation, renal clearance, and protein binding of sulphamerazine, N4‐acetylsulphamerazine, and N4‐trideuteroacetylsulphamerazine in ‘fast’ and ‘slow’ acetylators
Authors: Vree Tom B. , Hekster Chiel A. , Baakman Margriet , Janssen Tom , Oosterbaan Marijn , Termond Emiel , Tijhuis Marian 
Published: October 2006

AbstractSulphamerazine shows a clear acetylator phenotype. The half‐life of elimination of sulphamerazine is 12 h in ‘fast’ and 24 h in ‘slow’ acetylators. N4‐Acetylsulphamerazine is eliminated biphasically, characterized by half‐lives of 5 and 12 h in ‘fast’ and 5 and 24 h in ‘slow’ acetylators.Protein binding of sulphamerazine (86 per cent) and N4‐acetylsulphamerazine (92 per cent) is independent of acetylator phenotype or the origin of the compound, whether it is present in the body as parent compound or metabolite. The renal clearance of sulphamerazine (20ml min −1) and N4‐acetylsulphamerazine (300–500 ml min−1) is independent of the acetylator type and the origin of the compound.The existence of an acetylation‐deacetylation equilibrium in the metabolism of sulphamerazine has been demonstrated with the test drug N4‐trideuteroacetylsulpha‐ merazine, which inhibits the renal excretion and clearance of N4‐acetylsulphamerazine.
First‐pass elimination of salicylamide in man following oral and rectal administration
Authors: de Boer A. G. , Breimer D. D. , Gubbens‐Stibbe J. M. , Bosma A. 
Published: October 2006

AbstractIn order to study the avoidance of hepatic first‐pass elimination following rectal administration, 500 mg of salicylamide (SAM) were given orally and rectally to man. Plasma SAM concentrations were measurable following oral administration, but following rectal administration SAM concentrations were either very low or not detectable. The mean excretion of SAM sulphate (SAMS) and SAM glucuronide (SAMG) in the urine following oral and rectal administration was 71·3 per cent and 45·6 per cent respectively. Increasing the oral and rectal dose (1500 mg of SAM, solution) showed that the mean AUC values were 911 and 144 μg min ml−l, respectively. The mean urinary excretion of SAMS plus SAMG following oral and rectal administration was 82·0 and 75·6 per cent respectively; the mean plasma elimination half‐lives were 31 and 40 min, respectively, while the mean urinary elimination half‐lives were 63 and 73 min, respectively.
Pharmacokinetics of glucuronidation of propranolol following oral administration in humans
Authors: Midha K. K. , Roscoe R. M. H. , Wilson T. W. , Cooper J. K. , Loo J. C. K. , Ho‐Ngoc A. , McGilveray I. J. 
Published: October 2006

AbstractPharmacokinetic and bioavailability parameters of propranolol were estimated in 10 healthy adult subjects after single oral doses of two commercial tablet formulations of propranolol hydrochloride (2 × 40 mg). Plasma concentrations of propranolol were determined by a high‐performance liquid‐chromatographic (HPLC) assay. Peak plasma concentrations of propranolol glucuronide were 6·8 times those of the corresponding peak propranolol plasma concentrations. The mean resident time (MRT) of propranolol and of propranolol glucuronide was determined for each subject for both formulations. The MRT of the parent drug was found to be longer than the MRT of the glucuronide metabolite for each of the subjects examined. Statistical moment analysis indicated that this phenomenon is attributable to extensive presystemic glucuronidation of the parent drug.
The Wagner‐Nelson method applied to a multicompartment model with zero order input
Authors: Wagner John O. 
Published: October 2006

AbstractIt is shown that the Wagner‐Nelson absorption method provides zero‐order input rate constants exactly, or with small error, in a large number of cases where the two‐compartment open disposition model applies. Factors affecting the accuracy of the method were studied with error‐free simulated data. The method was applied to real data for three drugs. With ethanol infused over 2 h in eight human trials the estimated rate constant averaged 99·6 per cent of the known rate constant with a coefficient of variation of 6·86 per cent. With pindolol infused over 3 h in five human subjects the estimated rate constant averaged 98·7 per cent of the known rate constant with a coefficient of variation of 22·5 per cent. With theophylline administered orally in a sustained‐release form to seven human subjects the Wagner‐Nelson method provided estimated zero‐order rate constants which averaged 95·8 per cent of those estimated by an exact two‐compartment absorption equation with a coefficient of variation of 38·1 per cent (in this case bolus intravenous data were available for the same subjects).
The pharmacokinetics of HI‐6 in beagle dogs
Authors: Simons Keith J. , Briggs Colin J. 
Published: October 2006

AbstractThe pharmacokinetics of HI‐6 were studied following intravenous administration to beagle dogs (n = 7). The bioavailability of two different strength intramuscularly administered doses was also determined in the same animals. After a 20 mg kg−1 intravenous dose, the mean (±S.D.) initial HI‐6 plasma concentration was 93·1 ± 10·μg ml−1. The mean half‐life was 48·2±17·7 min, the mean total body clearance was 5·16 ± 0·81 ml min−1 kg−1, the mean apparent volume of distribution was 0·37·0±20 1 kg−1 and 61·2±14·6 per cent of the dose was excreted as unchanged drug. The pharmacokinetic constants calculated following the 20 mg kg−1 intramuscular doses of 250 and 25 mg ml−1 solutions were not significantly different from those obtained following the intravenous dose. Also, the areas under the plasma concentration versus time curves were not significantly different indicating 100 per cent bioavailability from the intramuscular route of administration.
Comparative pharmacokinetic analysis of a novel sustained release dosage form of valproic acid in dogs
Authors: Bialer Meir , Friedman Michael , Dubrovsky Joseph 
Published: October 2006

AbstractA new sustained release dosage form of valproic acid (VPA) was developed. The new sustained release dosage form was administered (twice, with and without food) to five dogs in comparison to a standard tablet (Depakine, Labaz) and an i.v. preparation of the drug. Drug level monitoring in the plasma was performed by a GLC assay. Results indicate that the sustained release formulation exhibited a more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion, and showed an overall bioavailability of 0·84 (95 per cent C.I. = 0·72, 0·96) relative to an equivalent dose of a conventional tablet.
Bioavailability studies with etodolac in dogs and man
Authors: Kraml M. , Cosyns L. , Hicks D. R. , Simon J. , Mullane J. F. , Dvornik D. 
Published: October 2006

AbstractThe effects of formulation, particle size, coadministration of food, antacids, or antiulcer agents on the bioavailability of etodolac (ULTRADOL®, 1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐acetic acid), a novel non‐steroidal anti‐inflammatory agent, have been evaluated in dogs and man. The effects of dosage regimen and/or repetitive dosing on bioavailability were also determined. In man, capsule and tablet dosage forms containing micronized etodolac were shown to have a bioavailability (AUC) equal to that of the reference etodolac solution. Etodolac from tablets and capsules was rapidly absorbed since only minor decreases in Cmax and increases in tmax were observed compared to the etodolac solution. In a comparison of regular and micronized etodolac dosage forms, both in dogs and man, similar findings, i.e. no change in AUC but small parallel changes in Cmax and tmax, were noted. Administration of etodolac with food had no effect on etodolac bioavailability in dogs but tended to cause a delay in its absorption. Coadministration of an antacid, magaldrate, or the antiulcer agent, sucralfate, had no effect on the bioavailability of etodolac in dogs, although with the latter, a significant reduction in Cmax was noted. In man, etodolac may be administered as a single bolus dose or in divided (b.i.d.) doses without any loss in bioavailability. With either regimen, on repeat administration for 7 days, no etodolac accumulation was noted.
The pharmacokinetics of intramuscular gold sodium thiomalate in normal volunteers
Authors: Massarella Joseph W. , Waller Elaine S. , Crout James E. , Yakatan Gerald J. 
Published: October 2006

AbstractFour normal male volunteers participated in a study designed to examine the disposition of gold given intramuscularly as gold sodium thiomalate. Blood samples were collected for 32 days following the administration of 10 mg of gold sodium thiomalate. Plasma gold concentrations were determined by atomic absorption spectrometry. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log‐linear phases corresponded to a mean disposition half‐life of 25 days. Apparent total body clearance of gold was 7·0 ± 0·6 ml kg−1 day−1 and the apparent volume of distribution was 0·26 ± 0·051 kg−1. These pharmacokinetic data are in contrast to previous data from other investigators who have reported half‐lives of approximately 5 days. Data from the current study provide a sound rationale for the currently used empiric dosing regimens.
Pharmacokinetic and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers
Authors: Caille G. , Du Souich P. , Spenard J. , Lacasse Y. , Vezina M. 
Published: October 2006

AbstractZopiclone is a new sedative showing a rapid onset of hypnotic effect and a relatively short duration of action. The goal of this study was to assess the kinetic parameters of zopiclone and its interaction with trimipramine when administered concomitantly. Ten normal subjects each received doses of zopiclone (7·5 mg), trimipramine (50 mg), and zopiclone (7·5 mg) + trimipramine (50 mg) orally at 7‐day intervals. The absorption of zopiclone was rapid, the observed plasma peak concentration and 95 per cent of all absorption occurring within one hour. The average elimination half‐life was 3·8 ± 0·2 h. The volunteers reported a bitter taste at an average of 24 min after zopiclone administration at which time concentrations in saliva were approximately 50 ng ml−1. Trimipramine decreased the relative bioavailability determined for zopiclone by 13·7 per cent, while zopiclone decreased the relative bioavailability of trimipramine by an average of 26·6 per cent, although neither of these changes was statistically significant (p > 0·05); there were no substantial changes in other kinetic parameters. It is concluded that zopiclone presents advantages over some other sedative drugs as it is rapidly absorbed and eliminated. When zopiclone is administered with trimipramine, the decrease in the relative bioavailability of trimipramine may be clinically significant.
Comparative bioavailability study of two tablet formulations of cimetidine
Authors: Berardi R. R. , Cohen I. A. , Hyneck M. L. , Lockwood G. F. , Shukla U. A. , Sakmar E. , Wells J. J. , Wagner J. G. 
Published: October 2006

AbstractA two‐way crossover bioavailability study of two commercial cimetidine formaulations was performed on 24 healthy male volunteers. Drug was administered after an overnight fast and plasma samples were withdrawn periodically for 12 h. Urine was collected throughout the study period. Results indicated that the two formulations were bio‐equivalent since no statistically significant difference in means was detected for any of the parameters studied. Extensive interpatient variation in cimetidine blood concentration was observed during both treatments.
Comparative pharmacokinetics of ketoprofen derived from single oral doses of ketoprofen capsules or a novel sustained‐release pellet formulation
Authors: Houghton G. W. , Dennis M. J. , Rigler E. D. , Parsons R. L. 
Published: October 2006

AbstractNine healthy male volunteers took part in a crossover study to compare the pharmacokinetics of ketoprofen after administration of a single oral dose (200 mg) of ketoprofen as ‘Orudis’ capsules of encapsulated stustatained‐release pellets, ‘Oruvail’ .The mean ± standard deviation values for highest observed plasma ketoprofen concentrations were determined by high performance liquid chromatography to be 23 ± 11 μg ml−1 at 0±82 ± 0±18 h after dosing with ketoprofen capsules and 3·5 ± 1·0 μg ml−1 at 4·9 ± 1·0 h after dosing with sustained‐release pellets. The apparent ketoprofen elimination half‐lives after these treatments were 3·3 ± 1·2 h and 8·4 ± 3·4 h, respectively. The systemic availability of ketoprofen was essentially the same after each treatment.Administration of sustained‐release pellets (containing 200 mg ketoprofen) once every 24 h is predicated to produce similar average and markedly higher minimum plasma ketoprofen concentrations than are produced by ketoprofen capsules (100 mg) every 12h, and similar minimum plasma ketoprofen concentrations to those achieved by dosing ketoprofen capsules (50 mg) every 6 h.Once‐daily administration of a non‐steroidal anti‐inflammatory agent has an obvious therapeutic advantage over more frequent dosing. This study suggests that the sustained‐release pellet formulation described herein is a suitable formulation for once‐daily administration of ketoprofen.
Pharmacokinetics of nalidixic acid associated with sodium citrate
Authors: Ferry N. , Cuisinaud G. , Sassard J. , Pozet N. , Zech P. Y. 
Published: October 2006

AbstractA pharmacokinetic study of sachets containing nalidixic acid (0·66 g) associated with sodium citrate (3·75 g)—NSC—was carried out in 10 healthy volunteers in order to determine the influence of the urine alcalinization due to sodium citrate on the elimination of nalidixic acid (NA) and its 7‐hydroxy (HNA) and 7‐carboxy (CNA) derivatives. Urine alcaliniztion enhanced markedly the urinery excretion of HNA, but not of NA and CNA. The urinary concentrations of bacteriologically active compounds—NA + HNA—remained above five times their minimum inhibitory concentration for 10 h following each dose. After a 3‐day treatment using NSC three times daily there was no significant accumulation of NA and derivatives in the plasma and no significant change in their kinetics. Finally, from a pharmacokinetic viewpoint, the daily administration of 3 sachets of NSC each containing 0·66 g of NA seems valuable in the treatment of urinary tract infections.
In vitro and in vivo evaluation of controlled‐release and enteric‐coated formulations of sodium salicylate
Authors: Borgström Lars , Ekman Bo , Larsson Hans , Leden Ido , Lindahl Åke , Melander Arne , Wålin‐boll Elisabeth 
Published: October 2006

AbstractThe bioavailability and pharmacokinetics of salicylic acid (SA) were studied after single and multiple doses of a new slow‐release formulation, based on porous membrane diffusion of sodium salicylate (NaSA). A solution of NaSA and an enteric‐coated tablet of NaSA were used for comparison. Dissolution rate studies were carried out at various pH values, and both solid formulations showed pH‐dependent release rates. The entericcoated tablet released its content rapidly at intestinal pH but slowly and irregularly at gastric pH. The dissolution from the controlled‐release formulation at intestinal pH was completed after 6 h and the drug was delivered at a constant rate. At gastric pH the release rate was lower but complete release was obtained within 24h. The novel formulation appeared to offer complete bioavailability of SA and an even and sustained release of SA, allowing twice‐daily medication without increased fluctuations in SA concentrations.
A model describing the disposition of phenytoin in isolated rat hepatocytes
Authors: Morais José A. , Wagner John G. 
Published: October 2006

AbstractThe use of isolated rat hepatocytes in studies of drug metabolism has become well documented in the past few years. However, in part because of modelling difficulties due to the simultaneously occurring substrate transferring processes, its predictability of in vivo situations has not been emphasized. Much controversy surrounds the metabolism of phenytoin (5,5‐diphenylhydantoin), a widely used anticonvulsant, and an appropriate pharmacokinetic model to describe the disposition of this drug still lacks general acceptance. In the present study, metabolism of phenytoin in the isolated rat hepatocyte system was followed by assaying either the unchanged drug or the pooled metabolites in both the suspending medium and the cells. A model was developed which can describe the time course of the different species sampled. Inhibition of biotransformation by the major metabolic product [5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin or p‐HPPH] and the uptake and release of the latter were also studied, in order to elucidate the role of product inhibition in determining the dose‐dependent pharmacokinetic behavior of the drug. The results obtained strongly suggest that only concentrations of p‐HPPH higher than the ones attained by phenytoin biotransformation alone can significantly inhibit the main enzymatic reaction.
The metabolic fate of 14C‐oxaprotiline · HCl in man. III. Stereospecific disposition
Authors: Dieterle W. , Faigle J. W. , Küng W. , Theobald W. 
Published: October 2006

AbstractThe disposition of the enantiomers of oxaprotiline has been investigated after single 100 mg oral doses of racemic 14C‐labelled oxaprotiline · HC1 in two healthy subjects.Absorption was complete. Peak blood concentrations of total 14C were 804 and 1010 ng equiv.g−1 after 4–6 h in the two subjects. After 9 days 85 and 80 per cent of the dose were excreted in urine, and a total of 93 and 87 per cent were found in the excreta. Mean peak blood concentrations of unchanged S(+)‐ and R(–)‐oxaprotiline amounted to 25 and 10 ng g−1 before, and 474 and 422 ng g−1 after acid hydrolysis (free plus O‐glucuronide). The mean blood half‐lives of the S(+) and R(–) isomers were 22 and 23 h.Direct O‐glucuronidation is the major metabolic pathway and N‐demethylation a minor one. The former is more marked with the S(+) isomer and the latter with the R(–) isomer. For oxaprotiline, the AUC‐ratio of S(+) to R(–) was 2·2 before and 1·4 after hydrolysis. For desmethyl oxaprotiline the corresponding ratio was 0·8 after hydrolysis.In urine, 0·8 and 0·5 per cent of total 14C were present as unchanged S(+)‐ and R(–)‐oxaprotiline. After acid hydrolysis of the O‐glucuronides, the enantiomers account for 44·7 and 37·1 per cent. The O‐glucuronides of S(+)‐ and R(–)‐desmethyl oxaprotiline account for 4·6 and 5·7 per cent.
Effect of liposomal surface charge on the pharmacokinetics of an encapsulated model compound
Authors: Abraham Isaac , Goundalkar Ashok , Mezei Michael 
Published: October 2006

AbstractThe pharmacokinetics of 3H‐Triamcinolone Acetonide‐21‐palmitate entrapped in liposomes with neutral, negative and positive surface charge was investigated in the male New Zealand White rabbit after a single intravenous bolus injection. Drug concentration–time data monitored in whole blood showed bi‐exponential decay and were analysed by a least‐squares regression analysis procedure to obtain pertinent pharmacokinetic parameters. The significance of the observed differences in the pharmacokinetics after administration of each type of liposome was assessed by the Analysis of Variance test method. Significant differences (p < 0·05) were found in α, β, (t0·5)α, K12, and Vc. Positive liposomes apparently encountered a larger initial apparent volume of distribution than the neutral or negative type, and consequently exhibited demonstrably lower initial blood drug concentration, (Cb)0. Liposomes with different surface properties were removed from circulation at different rates and this resulted in significant difference (p < 0·01) in the concentration of circulating liposomes an hour following injection of each type of liposome. A mean of 66 per cent of the initial concentration of positive liposomes remained in circulation an hour after injection whereas 11 and 23 per cent respectively of the neutral and negative type remained in circulation during the same time period. Liposomes with different surface properties apparently exhibited similar total body clearance of the encapsulated compound.
Valproic acid and active unsaturated metabolite (2‐EN): Transfer to mouse liver following human therapeutic doses
Authors: Nau Heinz , Loscher Wolfgang 
Published: October 2006

AbstractThe transfer of valproic acid (VPA, 2‐propylpentanoic acid) and its unsaturated active metabolite (2‐en, 2‐propyl‐2‐pentenoic acid) from plasma to liver has been studied in the mouse between 2 min and 6 h following oral administration of 50 mg of the sodium salts per kg body weight. Transfer of both compounds was extremely rapid. Liver concentrations of VPA were higher than those in plasma, while liver concentrations of 2‐en were lower than those in plasma. The low hepatic levels of 2‐en may be explained by extensive plasma protein binding of this metabolite. The liver/plasma concentration ratios were concentration‐dependent, indicating the presence of active transport mechanisms and/or saturation of plasma protein binding. Our results indicate that 2‐en should be further studied in regard to its potential for the induction of liver toxicity. The desirable low level of 2‐en reached in the liver, seen together with previously observed favourable‐anticonvulsant profile and low teratogenicity, would indicate that this compound may be a valuable alternative antiepileptic agent.
Pharmacokinetics of valproic acid in volunteers after a single dose study
Authors: Bialer Meir , Hussein Ziad , Raz Itamar , Abramsky Oded , Herishanu Yuval , Pachys Freddy 
Published: October 2006

AbstractThe pharmacokinetics of valproic acid (VPA) was investigated in six healthy volunteers. This was done by monitoring total and free (unbound) valproic acid levels in the serum, and the amount of one of its metabolites, VPA glucuronide, in the urine as a function of time, after a single dose administration of the parent drug. VPA half‐life calculated from the urine data of the metabolite was shorter than the half‐life calculated from the blood data. About 15 to 20 per cent of the administered oral dose of VPA was excreted in the urine as VPA glucuronide. The average free fraction of VPA obtained in this study, by using the EMIT technique, ranged from 1.5 to 11.5 per cent with a mean value of 4.9 per cent.