bluuebunny/crossref_metadata_2025 huggingface dataset:
Antipyrine metabolite kinetics in rats: Studies on dose and time dependence
Authors: Rhodes John C. , Houston J. Brian
Published: October 2006

Antipyrine metabolite kinetics have been investigated in the rat with respect to dose and time dependence. The metabolic pathways, 4‐hydroxylation, benzylic oxidation, and N‐demethylation, are of equal quantitative importance (approximately 20 per cent of dose) and show no dose dependence over the range 25–500 mg kg−1. By using [N‐methyl‐14C]‐antipyrine the single carbon fragment lost by N‐demethylation may be monitored as 14CO2. Serial sampling of 14CO2 exhalation rate provides a half‐life estimate which, according to theoretical principles, reflects the antipyrine plasma half‐life. When both half‐lives were measured in the same animals a statistically significant correlation was evident. At doses of 250 mg kg−1 and 500mg kg−1 there is an increase in CER half‐life (218 and 303 min respectively) when compared to a dose below 100mg kg−1 (152 min). The metabolite formation rate constants are decreased accordingly at the high doses but are invariant over the dose range 25–100mg kg−1. Although inter‐rat variation in antipyrine metabolite kinetics was substantial, intra‐rat variability was small. The non‐invasive nature of determining antipyrine metabolite kinetics via breath and urine analysis provides a potentially useful animal model system to investigate the factors influencing hepatic mixed function oxidase activity in vivo.
Urinary pH and plasma levels of salicylate after administration of different buffered acetylsalicylic acid formulations
Authors: Bogentoft C. , Dahl G. , Magnusson A.
Published: October 2006

In a controlled cross‐over study comprising eight healthy subjects of effervescent acetylsalicylic acid (ASA) and an experimental ASA formulation were compared with unbuffered ASA and placebo concerning effects on the urinary pH within a dosage interval after 2 days' medication with 3 g ASA daily. The effects on the urinary pH were related to the morning plasma salicylate concentrations observed.

Both the buffered formulations significantly increased the median pH of the period studied compared to unbuffered ASA, the effervescent by 1·5 units and the experimental by 0·6 units. Unbuffered ASA significantly decreased the median pH compared to placebo. Those subjects with the most acidic urine during placebo treatment showed the most pronounced pH elevations due to effervescent ASA. The plasma salicylate concentration was significantly lower with the effervescent formulation compared with unbuffered ASA, but there was no statistical difference between the experimental tablet and unbuffered ASA.

The variable effects on the urinary pH and the plasma salicylate concentrations induced by the two buffered preparations are explained by the different absorbabilities of the buffering agents included. The results presented are consistent with recommendations not to use bicarbonate‐containing ASA formulations continuously when high plasma levels are desirable.
Steady‐state distribution volume in physiologic multi‐organ systems
Authors: Weiss Michael
Published: October 2006

A unique definition of the apparent volume of distribution at steady‐state is presented which is consistent with the realistic concept of blood concentration differences within the circulatory system. A physiologically based pharmacokinetic model consisting of eliminating and non‐eliminating organs is used to predict the effect of drug elimination upon the steady‐state distribution volume.
The Statistical Package for the Social Sciences (SPSS) as an adjunct to pharmacokinetic analysis
Authors: Mather Laurence E. , Austin Kevin L.
Published: October 2006

Computer techniques for numerical analysis are well known to pharmacokineticists. Powerful techniques for data file management have been developed by social scientists but have, in general, been ignored by pharmacokineticists because of their apparent lack of ability to interface with pharmacokinetic programs. Extensive use has been made of the Statistical Package for the Social Sciences (SPSS) for its data handling capabilities, but at the same time, techniques have been developed within SPSS to interface with pharmacokinetic programs of the users' choice and to carry out a variety of user‐defined pharmacokinetic tasks within SPSS commands, apart from the expected variety of statistical tasks. Because it is based on a ubiquitous package, this methodology has all of the benefits of excellent documentation, interchangability between different types and sizes of machines and true portability of techniques and data files. An example is given of the total management of a pharmacokinetic study previously reported in the literature by the authors.
Effect of food and an antacid on quinidine bioavailability
Authors: Ace Louis N. , Jaffe James M. , Kunka Robert L.
Published: October 2006

Two 200 mg quinidine sulfate tablets were administered to nine healthy male subjects in the fasting state, immediately after a balanced meal, and with 30ml of aluminum hydroxide gel using a complete crossover design. Serum and urine samples were taken over 32 and 60 h respectively. Quinidine concentrations were measured using a high‐performance liquid chromatography assay specific for quinidine. Computer fitting of the data to several models indicated that a one‐compartment model with zero‐order absorption and a lag time best fit all the data. Quinidine elimination and urine pH were unaffected by the study conditions. While the maximum serum concentration (Cmax) and area under the serum concentration—time curve (AUC) were unaffected by administration of quinidine with food or antacid, there was a 44 per cent increase (p < 0·10) in time to Cmax (tmax) following quinidine administration with food. Thus, while the extent of quinidine absorption was unaffected by food or the antacid used, the rate of quinidine absorption was significantly reduced by food as reported earlier.
Rectal versus oral absorption of codeine phosphate in man
Authors: Moolenaar Frits , Grasmeijer Germ , Visser Jan , Meijer Dirk K. F.
Published: October 2006

Rectal absorption of codeine phosphate from various dosage forms was studied in man. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. The plasma concentrations of codeine were measured by means of HPLC analysis after a single dose of 60 mg codeine phosphate in a cross‐over study in 7 volunteers. Compared with oral dosing rectal absorption from an aqueous solution or a fatty suppository produced an almost identical plasma concentration profile with similar interindividual variations. Comparing the absorption rate characteristics it appeared that rectal absorption from an alkaline solution containing codeine phosphate proceeded significantly (P < 0·05) more rapid than after oral dosing. No essential difference in bioavailability was observed between the various rectal and oral dosage forms.
Significance of ratios of different volumes of distribution in pharmacokinetics
Authors: Wagner John G.
Published: October 2006

Multicompartmental 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

Sulphamerazine 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

In 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

Pharmacokinetic 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

It 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

The 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

A 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

The 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

Four 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

Zopiclone 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

A 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

Nine 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

A 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

The 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

The 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

The 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

The 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

The 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

The 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.
The effect of food and antacid on the absorption of fendosal
Authors: Wills Robert J. , Velagapudi Raja B. , Puri Surendra K. , Yakatan Gerald J.
Published: October 2006

Fendosal(200 mg) was given orally to each of two separate groups of twelve healthy male volunteers on separate occasions to assess the influence of food or antacid on the bioavailability of fendosal. Blood samples (20ml) were drawn during 12 hours postdosing and fendosal plasma concentrations were quantitated by a validated fluorescence technique. Food was shown to have no significant effect (p >0.05) on fendosal bioavailability. However, the bioavailability of fendosal in the presence of an antacid was reduced by 80 per cent. In vitro studies suggested that a complexation between unionized fendosal and the metal ions contained in the antacid may be responsible for the decrease in the rate and extent of absorption observed in vivo.
Bioequivalence of a sustained‐release isosorbide dinitrate formulation at steady‐state
Authors: Taylor T. , Chasseaud L. F. , Major R. M. , Leaf F. C. , Bonn R. , Darragh A. , Lambe R. F.
Published: October 2006

Isosorbide 2,5‐dinitrate and its pharmacologically active metabolites, isosorbide 2‐nitrate and isosorbide 5‐nitrate, in plasma accumulated to the predicted steady‐state after five consecutive oral doses of sustained‐release tablets containing 40 mg isosorbide dinitrate at 12‐h intervals and after five consecutive oral doses of reference standard‐release tablets containing 20 mg at 6‐h intervals to 12 subjects in a crossover study. The comparative bioavailability of isosorbide dinitrate, isosorbide 2‐nitrate and isosorbide 5‐nitrate from the sustained‐release tablet was 110 per cent (p > 0.05), 89 per cent (p > 0.05), and 89 per cent (p < 0.05), respectively, of that from the reference standard‐release tablet. The isosorbide dinitrate plasma level data were the more variable, as expected for a drug of low systemic availability subject to extensive first‐pass elimination. The posterior probability that the true bioavailability of isosorbide dinitrate was included within the usually accepted limits of 80–120 per cent was 0.74, a value which is probably insufficient to justify claims of bioequivalence with the reference formulation in respect of extent of availability. In contrast, the posterior probability that the bioavailability of the metabolites isosorbide 2‐ and 5‐nitrate was included within these limits was 0.90 and 0.98, respectively. On the basis of the mononitrate data, these two formulations may be judged bioequivalent in respect of extent of availability despite a formal statistically significant formulation‐related effect in the analysis of variance of the isosorbide 5‐nitrate bioavailability data. Claims of bioequivalence of isosorbide dinitrate sustained‐release formulations may be more economically justified by analysis of the mononitrate plasma concentrations, although concentrations of the formulated parent dinitrate should also be known.
Lack of effect of liver disease on the pharmacokinetics of acebutolol and diacetolol: A single dose study
Authors: Zaman R. , Jack D. B. , Wilkins M. R. , Kendall M. J.
Published: October 2006

The pharmacokinetics of acebutolol and its major metabolite, diacetolol, following a single 400 mg oral dose, were investigated in patients with liver disease. No significant differences were found in any of the parameters measured.
A pharmacokinetic comparison of cephalexin and cefadroxil using HPLC assay procedures
Authors: Welling Peter G. , Selen Arzu , Pearson John G. , Kwok Florence , Rogge Mark C. , Ifan Agber , Marrero Diana , Craig William A. , Johnson Curtis A.
Published: October 2006

The pharmacokinetics of cephalexin and cefadroxil were compared following single 500 mg oral doses to 12 healthy male volunteers. Doses were administered after an overnight fast according to a crossover design. Plasma and urinary levels of both compounds were determined by HPLC procedures. Cephalexin was absorbed rapidly, achieving a mean peak plasma level of 17.5 μg ml−1 at 1 h, compared to 16 μg ml−1 at 1.8 h for cefadroxil. Elimination half‐lives of cephalexin and cefadroxil were 0.7 and 1.1 h, respectively. The area under the cefadroxil plasma curve was significantly larger than that for cephalexin. However, after allowing for differences in elimination rate constants and assuming equal distribution volumes, plasma data indicated the compounds were equally well absorbed. Only 70 per cent of cefadroxil was recovered in urine compared to 87 per cent of cephalexin during the 12 h following drug administration. The therapeutic significance of the different pharmacokinetic characteristics of cephalexin and cefadroxil, if any, may be a function also of their pharmacologic activity and/or the sensitivity of the target organism.
Concentration‐dependent clearance of procainamide in normal subjects
Authors: Coyle James D. , Boudoulas Harisios , Mackichan Janis J. , Lima John J.
Published: October 2006

Four normal volunteers each received two intravenous doses of PA. The mean low dose was 3.30 mg kg−1 (infused over 20 minutes) while the mean high dose was 12.5 mg kg−1 (infused over 60 minutes). Blood samples were collected for 12 hours and urine was collected for 48 hours after each dose. PA concentrations were determined by both HPLC and fluorescent immunoassay methods. The reported concentrations and pharmacokinetic parameters are from the HPLC data unless otherwise indicated. The mean peak serum PA concentrations resulting from the low and high doses were 3.18 and 9.07 μg ml−1, respectively. Total PA clearance averaged 763 ml min−1 and 577 ml min−1 while renal clearance averaged 360 ml min−1 and 318 ml min−1 after the low and high doses, respectively. Concentration‐dependent decreases in nonrenal PA clearance ranged from 31 to 43 percent (p < 0.05) in the four subjects. Total clearance decreases ranged from 4.7 to 36 per cent (p < 0.05). Differences between doses in renal clearance, elimination rate constant, and volume of distribution were not statistically significant. This study demonstrates that the nonrenal and total clearances of PA are concentration‐dependent in normal subjects at therapeutic plasma PA concentrations and suggests that the total clearance changes are of sufficient magnitude to be clinically important.
Effects of ibuprofen on the disposition kinetics of phenytoin in pregnant rats
Authors: Cleveland Patricia A. , Ueda Clarence T.
Published: October 2006

The effects of ibuprofen on maternal phenytoin pharmacokinetics and fetal phenytoin acquisition were investigated in 19‐day gestation Sprague—Dawley rats. A 5 mg kg−1 bolus injection of 14C‐phenytoin was given with and without (control) pretreatment with 12.5 mg kg−1 of ibuprofen. Maternal plasma and fetal whole body samples were obtained at various times after the phenytoin bolus and evaluated simultaneously using a three‐compartment maternal‐fetal model. Ibuprofen pretreatment increased the maternal plasma clearance of phenytoin about three‐fold and the overall apparent volume of distribution almost four‐fold. No changes in the volume of the maternal central compartment or terminal first‐order disposition rate constant were observed. Additionally, the maternal‐to‐fetal clearance of phenytoin was not altered in the ibuprofen‐treated rats. No differences in the apparent fetal volume of distribution or areas under the fetal phenytoin concentration‐time curves were observed between the control and ibuprofen‐treated rats. The results of this study were consistent with ibuprofen‐induced alterations in organ and tissue blood perfusion and demonstrated that, while the maternal disposition kinetics of phenytoin were altered by sodium ibuprofen coadministration, the maternal changes did not affect the extent of fetal exposure to phenytoin.
Michaelis—Menten elimination kinetics: Areas under curves, steady‐state concentrations, and clearances for compartment models with different types of input
Authors: Wagner John G. , Szpunar Gregory J. , Ferry James J.
Published: October 2006

For single bolus administration, intermittent bolus administrations to steady‐state, a single dose as a zero order input, intermittent zero order inputs to steady‐state, and continuous zero order input to steady‐state, and for both simple Michaelis—Menten elimination and parallel Michaelis—Menten and first order elimination, the appropriate equations are given for the areas, AUC 0–∞ or AUC 0–τ, steady‐state concentrations, and clearances. Some 20 new equations have been derived. For the case of first order input and Michaelis—Menten elimination, no solution is given but the effect of input rate on systemic availability is reported following some numerical integrations.

The effect of slow input in reducing systemic bioavailability when Michaelis—Menten elimination kinetics are operative is stressed and the implications of this in the field of sustained‐release medication mentioned.
Pharmacokinetics of theophylline in protein‐calorie malnutrition
Authors: Jung Donald
Published: October 2006

The influence of protein‐calorie malnutrition (PCM) on the disposition of theophylline was investigated in male Sprague‐Dawley rats fed for four weeks on a 23 per cent (control) or 5 per cent (low) protein diet ad lib. Dietary protein deficiency led to a decrease in body weight gain, plasma proteins. albumin, microsomal proteins, and cytochrome P‐450. After intravenous administration of aminophylline equivalent to 10 mg kg−1 theophylline, the average mean residence time (MRT) was 58 per cent higher in the protein‐deficient rats, while the total plasma clearance (CI) per kilogram of body weight and elimination rate constant (k) were decreased by 39 per cent and 45 per cent, respectively, when compared to rats on a normal protein diet. No significant difference was found in the two groups of animals with respect to the apparent steady‐state volume of distribution (Vss). The present results suggest that the mechanism responsible for the observed pharmacokinetic changes in the protein‐deficient rats is related to the reduced amount and/or activity of the hepatic mixed function oxidases.
Effect of dietary mineral and vitamin D content and parathyroidectomy on the plasma disappearance rate of 1,25‐dihydroxy vitamin D3 in rats
Authors: Paulson Susan K. , Kenny Alexander D.
Published: October 2006

The plasma disappearance rate of 1,25‐dihydroxyvitamin D3 [1,25‐(OH)2 D3] was determined in rats after a single intravenous injection of the tritiated hormone. Tritiated 1,25‐(OH)2D3 (120 Ci mmol−1) was administered to rats at a dose of 400 000 dpm kg−1 body weight and the animals were bled between 0 and 8 hours. The dose was estimated to produce negligible perturbations in endogenous plasma levels of 1,25‐(OH)2D3. The plasma disappearance of 3H‐1,25‐(OH)2D3 occurred in two phases. The second phase plasma half‐life of 1,25‐(OH)2D3 in immature 25‐ to 35‐day‐old animals (4.7 hours) was significantly shorter than the second phase plasma half‐life of maturing 49‐ to 65‐day‐old animals (8.0 hours). Phosphorus deprivation for 12 days significantly prolonged the second phase plasma half‐life of 1,25‐(OH)2D3 from a control value of 4.9 hours to 10.4 hours. Parathyroidectomy, regardless of the plasma calcium concentrations, shortened the second phase plasma half‐life of 1,25‐(OH)2D3 from control values of 9.1 hours to 5.0 hours. Calcium deprivation for 7 days did not alter the second phase plasma half‐life of 1,25‐(OH)2D3. Vitamin D deprivation for 5 weeks increased the second phase plasma half‐life from 11.0 to 19.9 hours but the difference was not significant.
Pharmacokinetic evaluation of novel sustained‐release dosage forms of valproic acid in humans
Authors: Bialer Meir , Friedman Michael , Dubrovsky Joseph , Raz Itamar , Abramsky Oded
Published: October 2006

1. Five new sustained‐release dosage forms of valproic acid (VPA) were developed.

2. The new sustained‐release formulations were administered to six healthy subjects for comparison with a standard tablet and an i.v. preparation of the drug.

3. Three of the formulations exhibited a more prolonged and uniform absorption rate and yielded more sustained serum levels after ingestion. These three formulations maintained serum therapeutic levels of VPA for 24 h after a single oral administration of 1 g, and were bioequivalent to a marketed standard tablet of VPA.

4. The absorption profile of the various oral formulations was analysed pharmacokinetically, using the Loo‐Riegelman procedure.
Oral and rectal nalbuphine bioavailability: First‐pass metabolism in rats and dogs
Authors: Aungst Bruce J. , Lam Gilbert , Shefter Eli
Published: October 2006

The disposition of the narcotic antagonist/analgesic nalbuphine after i.v., oral, and rectal dosing was evaluated in rats and dogs. In both species nalbuphine had high systemic clearance and low oral bioavailability as a result of extensive first‐pass metabolism. Administration to a closed 2 cm length of rectum in rats resulted in complete bioavailability; first‐pass metabolism was circumvented. However, the extent of first‐pass metabolism increased when the dose was not restricted to the lower rectum. Rectal nalbuphine bioavailability in dogs from a solution or three suppository formulations was low and equivalent to oral bioavailability. This was probably because of upward spreading of the dose and subsequent first‐pass metabolism. Sodium salicylate, which has been shown to improve rectal absorption of other drugs, did not affect nalbuphine bioavailability rectally.
Comparative pharmacokinetics of midazolam and loprazolam in healthy subjects after oral administration
Authors: Jochemsen R. , Van Rijn P. A. , Hazelzet T. G. M. , Van Boxtel C. J. , Breimer D. D.
Published: October 2006

The pharmacokinetics of oral midazolam (Dormicum®, 15 mg) and loprazolam (Dormonoct®, 1 mg) were studied in eight healthy young volunteers in a cross‐over design. Plasma concentrations of midazolam were measured with a gas chromatographic method and loprazolam concentrations were determined by a radio‐receptor technique. Absorption of midazolam proceeded very rapidly (median tmax = 0.4 h) and a rapid onset of sedative action was observed. Loprazolam absorption was relatively slow (median tmax = 3 h) and its absorption profile was often irregular. Most subjects fell asleep before peak concentrations were reached. Median peak concentrations were 94 ng ml−1 and 3·1 ng ml−1 for midazolam and loprozolam, respectively. The median elimination half‐life of midazolam was 1·8 h and that of loprazolam 15 h. It is possible that the elimination half‐life of loprazolam as determined by radioreceptor assay is determined by active metabolites rather than by loprazolam itself. Midazolam elimination half‐life was the same when determined by radioreceptor assay or by GLC. There was no significant correlation between the half‐lives of the two drugs.
Novel assay and pharmacokinetics of levamisole and p‐hydroxylevamisole in human plasma and urine
Authors: Kouassi E. , Caillé G. , Léry L. , Larivière L. , Vézina M.
Published: October 2006

A new gas chromatographic method was developed for the quantification of levamisole in human plasma and urine, using a nitrogen–phosphorus flame ionization detector. The adsorption of the drug onto glass was prevented by treating the glassware with a siliconizing agent. The sensitivity of the assay was 10 ng ml−1 and as low as 2 ng ml−1 can be detected in plasma.

The urinary metabolite p‐hydroxylevamisole was analysed by high performance liquid chromatography with ultraviolet detection. The sensitivity of this assay was 0·50 μg ml−1.

Plasma and urinary concentrations of levamisole were determined in 10 healthy volunteers including seven men and three women following the administration of a single 150 mg dose of levamisole. Levamisole was rapidly absorbed (tmax 1·5 h), giving a peak plasma concentration of 716·7 ± 217·5 ng ml−1. The plasma elimination half‐life of levamisole was 5·6 ± 2·5 h. Only 3·2 ± 2·9 per cent of the oral dose was recovered as unchanged drug in the urine, suggesting the importance of clearance of levamisole by routes other than the kidney, and most probably by hepatic metabolism.

The urinary concentrations of p‐hydroxylevamisole were determined before and after hydrolysis of the urine samples with β‐glucuronidase, and the level of conjugation of the metabolite with glucuronic acid was then estimated. Cumulative recovery of the metabolite accounted for 1·6 ± 1·1 per cent and 12·4 ± 5.5 per cent of the oral dose of levamisole before and after hydrolysis, respectively, indicating that p‐hydroxylation is a relatively important route of metabolism of levamisole, and that the p‐hydroxylated metabolite is excreted mainly in conjugation with glucuronic acid.

Except for the absorption rate of levamisole which is approximately twice as rapid in women as in men, there is no marked difference in the pharmacokinetics of levamisole between healthy men and women.
The non‐linear pharmacokinetics of prednisone and prednisolone. I. Theoretical
Authors: Ferry James J. , Wagner John G.
Published: October 2006

Three simple linear and three simple non‐linear pharmacokinetic models are presented which incorporate the reversible metabolism that occurs between prednisone and prednisolone. Under steady‐state conditions it is possible to not only distinguish between the linear and non‐linear models but also to determine which particular model of each group applies to a given set of data. While the non‐linear conversion of prednisolone to prednisone is important in explaining the pharmacokinetics of prednisone in all three non‐linear models, the same is not true for prednisolone.