bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of urea: Development of a kinetic model for correlating dietary nitrogen intake and urea metabolism in chronic renal failure
Authors: Lee Ching‐San C.
Published: October 2006

A simple urea pharmacokinetic model is developed to define the multiple correlations among dietary nitrogen intake, urea generation rate, and serum urea nitrogen. Model‐based patient data are simulated during and between dialysis for serum urea nitrogen. Application of the kinetic model is demonstrated by retrospective fitting of serum urea nitrogen to the simultaneous equations which pertain to the model. The pharmacokinetic parameters obtained through the computer fitting can be integrated according to the mass balance equation to yield a quantitative solution to achieving the regulation of protein nitrogen intake. The kinetic approach is potentially advantageous over the conventional nitrogen balance method by virtue of its simplicity. Further validation of the pharmacokinetic model is required before its clinical application.
Pharmacokinetics of mepindolol administered alone and in combination with hydrochlorothiazide—a bioequivalence study
Authors: Krause W. , Lennert Chr.
Published: October 2006

The bioavailability and pharmacokinetics of 10 mg of mepindolol sulphate and of 25 mg of hydrochlorothiazide were compared in a cross‐over design in five healthy volunteers after the administration of either the single drugs (Corindolan® and Esidrix®) or in combination (Tenesor®).

Maximum concentrations of mepindolol in the plasma of 25 ng ml−1 were achieved 1·6 h after both treatments and the half‐life of disposition was calculated to be 4·5 h, being somewhat longer after the combination tablet. The amount of hydrochlorothiazide renally eliminated up to 48 h after drug intake was about 60 per cent of the dose. The half‐life of renal excretion was 3 h. The two formulations of mepindolol sulphate and hydrochlorothiazide proved to be bioequivalent with a tendency to better mepindolol bioavailability in the combination form.
Plasma levels of ethaverine after oral administration to humans
Authors: Meyer Marvin C. , Raghow Gursharan , Straughn Arthur B.
Published: October 2006

Fourteen healthy human subjects received a 200 mg oral dose of ethaverine hydrochloride as an elixir. Blood samples were obtained for 12 h after dosing. Plasma ethaverine concentrations were determined using a paired‐ion, reversed‐phase high performance liquid chromatographic method. Individual plasma concentration‐time profiles were fitted to a two‐compartment model with first‐order absorption. The ethaverine was rapidly absorbed, based on a time of maximum plasma concentration of 0·75 h, a time‐lag of 8·4min, and an apparent first‐order absorption half‐life of 8·6min. The mean terminal elimination half‐life was 3·3 h.
A second peak in uptake of gentamicin by rat kidney after cessation of treatment
Authors: Chareul C. , Faccini J. , Monro A. , Nachbaur J.
Published: October 2006

Gentamicin was administered s.c. to rats once daily for 7 days at 5 mg kg−1. At the end of this period renal concentrations of gentamicin declined from day 1 to day 5 post‐dosing, but showed a second peak on day 8, after which they declined again through days 16 and 22. This second peak coincided with a peak of mitotic activity in the kidney, suggesting that this organ, while recovering from gentamicin‐induced damage, passes through a temporary phase during which it has increased affinity for gentamicin.
A bioequivalency study of two trifluoperazine tablet formulations using ria and GC–MS
Authors: Midha K. K. , Hawes E. M. , Korchinski E. D. , Hubbard J. W. , McKay G. , Cooper J. K. , Roscoe R. M. H.
Published: October 2006

Two sensitive analytical procedures, a radioimmunoassay (RIA) and a mass fragmentographic (GC–MS) method, were used to quantitate plasma trifluoperazine concentrations over 24 h in five healthy male volunteers following single 5 mg doses of two trifluoperazine tablet formulations (A and B) in a two‐way cross‐over design. Bioavailability in terms of area under the plasma concentration versus time curve to 24 h or extrapolated to infinity, maximum plasma concentration and time to maximum plasma concentration using either RIA or GC–MS was not statistically significantly different from one formulation to the other. Also, there were no statistically significant differences between GC–MS and RIA values for AUC024 and Cmax for each of the two formulations examined. However, the mean AUC024 RIA/GC–MS ratios for formulations A and B were 3·1 and 3·4, respectively, while the mean Cmax RIA/GC–MS ratios were 1·7 and 2·1, respectively. These differences in AUC and Cmax are probably mainly due to the relative non‐specificity of the RIA antiserum. Thus, where GC–MS is preferred for pharmacokinetic studies, both analytical procedures can be used for comparative single‐dose bioequivalence studies of trifluoperazine. However, both the methods should be tested in patients in order to establish the suitability of one procedure over the other for the study of plasma level versus clinical response correlations.
Interaction of naproxen with cholestyramine
Authors: Calvo M. V. , Dominguez‐Gil A.
Published: October 2006

‘In vitro’ and ‘in vivo’ studies were used to determine the interaction of naproxen, an anti‐inflammatory agent, and cholestyramine, a hypocholesterolemic substance.

Cholestyramine shows a marked affinity for naproxen and the intensity of this is governed by the pH values. The maximum amount of naproxen adsorbed by the resin is close to 2·2 mMg−1.

The pharmacokinetics of naproxen was studied in eight healthy volunteers after concurrent oral administration in a single dose of 250 mg of naproxen and 4 g of cholestyramine. The resin causes an important delay in the incorporation of naproxen into the systemic circulation, though no significant modifications are seen to take place in any other pharmacokinetic parameters of the drug.
Bioavailability of nifedipine: A comparison between two preparations
Authors: Zylber‐Katz E. , Koren G. , Granit L. , Levy M.
Published: October 2006

In a random cross‐over study, eight healthy volunteers received single 10 mg doses of either nifedipine capsule (Adalat, Bayer) or nifedipine tablets (Taro) after an overnight fast. The areas under the serum concentration time curves were not significantly different (AUC0→ ∞ 319·8 ± 28·0 (SEM) ng ml−1 h−1 for capsules, 260·8 ± 15·3 ng ml−1 h−1 for tablets). The peak serum levels and the time of their occurrence were 162·4 ± 23·4 ng ml−1 at 30 min for capsules and 43·0 ± 3·0 ng ml−1 at 1–2 h for tablets, indicating that the absorption of nifedipine from the capsule is faster than from the tablet form. Clinical symptoms of vasodilation corresponded with the nifedipine peak levels. We conclude that although the bioavailability in general of the two preparations is similar, the therapeutic equivalence may differ. Depending on the therapeutic indication each preparation may have its merits.
Comparative bioavailability of two oral formulations of flurazepam in human subjects
Authors: Cooper Sam F. , Drolet Daniel , Dugal Robert
Published: October 2006

The systemic availability of an investigational oral formulation of flurazepam was compared to that of a commercially available product whose therapeutic efficacy has been well established by usage. The experiment was designed to dissociate formula on factors from all other sources of variation including differences between subjects, sexes, sequences of administration, experimental periods, as well as sex by sequence, sex by period, and sex by formulation interactions. Systemic availability was assessed by conventional pharmacokinetic techniques.

Pharmacokinetic interpretation and statistical analysis of plasma concentrations of flurazepam and its major blood metabolites namely N‐1‐hydroxyethylfurazepam and N‐1‐desalkylflurazepam as a function of time and of systemic availability indicators revealed a nearly identical biopharmaceutical behaviour for the two preparations. A significant difference could be seen in the plasma levels of N‐1‐desalkylfurazepam between male and female subjects. The results collectively indicate a very similar biopharmaceutical performance of the two oral formulations of flurazepam.
Effect of quinidine on the intestinal secretion of digoxin in guinea pigs
Authors: Schäfer S. G. , Fichtl B. , Doering W.
Published: October 2006

Following i.v. injection of digoxin (10 μg kg−1) the ratio between digoxin concentrations in the lumen of jejunal loops perfused in situ and in plasma (L/P) of guinea pigs increased linearily with time. After 3 h, L/P was 8·7, indicating net secretion of digoxin against a concentration gradient. In quinidine treated animals (100 mg kg−1 p.o., 2h before experiment) both the L/P ratio (5·7; p < 0·01) and the digoxin content of jejunal tissue (– 32 per cent; p < 0·01) were markedly reduced. It is suggested that quinidine reduces the extrarenal clearance of digoxin at least in part by inhibiting the intestinal secretion of this glycoside.
Pharmacokinetics of valpromide in dogs after various modes of administration
Authors: Bialer Meir , Rubinstein Abraham
Published: October 2006

Valpromide‐Depropylacetamide was administered to five dogs via five modes: Three oral formulations (solution, capsule, and enteric‐coated tablet), intravenous and intra‐muscular injections. No significant change in the terminal half‐life of valpromide could be observed after the various modes of administration in each dog. Valpromide was more rapidly absorbed after the administration of an oral solution than after i.m. injection. Similar data also were obtained for its metabolite—valproic acid. It was shown that valpromide in the dogs was partly biotransformed to valproic acid. The average fraction of valpromide that was transformed to valproic acid (fm) ranged from 30–35 per cent after all the oral and parenteral administrations, except for the enteric‐coated tablet, which showed a very low bioavailability of valpromide.
Effects of penicillins on binding of phenytoin to plasma proteins in vitro and in vivo
Authors: Arimori K. , Nakano M. , Otagiri M. , Uekama K.
Published: October 2006

Effects of penicillins on the binding of phenytoin to plasma proteins were examined in vitro and in vivo. The results from in vitro studies showed that the penicillins including oxacillin and dicloxacillin were effective in displacing phenytoin from its binding sites. In vivo, the total phenytoin concentration in serum decreased during penicillin administration, while the free phenytoin concentration increased. As a result, penicillins caused a significant increase in the apparent volume of distribution and in the total body clearance of phenytoin. These results can be explained on the basis of the displacement of phenytoin from its plasma protein binding site by penicillins.
Comparison of two enteric‐coated acetylsalicylic acid preparations by monitoring steady‐state levels of salicylic acid and its metabolites in plasma and urine
Authors: Edgar B. , Bogentoft C. , Lagerström P.‐O.
Published: October 2006

In a randomized three‐way crossover study, 12 healthy male volunteers were given multiple oral doses, i.e. 1·5 g b.i.d. for 7 days, of two different types of enteric‐coated acetylsalicylic acid (ASA) preparations, one being a conventional enteric‐coated tablet (ET) and the other enteric‐coated granules (EG) in a capsule; conventional ASA tablets were used as a reference. Plasma levels and excretion of salicylic acid and some of its metabolites were investigated under steady‐state conditions.

Plasma salicylic acid (SA) and salicyluric acid (SUA) levels were determined using a liquid chromatographic method. Two separate analyses were done to quantitate the metabolites in urine. SA, SUA, and gentisic acid were each assayed by the method used for plasma. Total salicylate was also determined.

There was no significant difference in urinary excretion of total salicylate between the three formulations. A diurnal variation in the excretion of SUA and SA in urine was found. The two enteric‐coated formulations provided significantly higher morning plasma concentrations than the conventional aspirin. The AUC was found to be significantly higher for ET than for the other two formulations. EG gave more uniform plasma levels during the studied 12‐h intervals and also less inter‐ and intra‐individual variations than ET, indicating that a b.i.d. regimen may be suitable for EG.
Comparison of the erythrocyte partitioning method with two classical methods for estimating free drug fraction in plasma
Authors: Trung A. Ho Ngoc‐Ta , Sirois G. , Dubé L. M. , McGilveray I. J.
Published: October 2006

A modification of the erythrocyte partitioning method for the rapid estimation of plasma‐free drug fractions (fu) is described and applied to five basic drugs. In the procedure, which uses readily available clinical laboratory equipment, fu is calculated from measurements of durg partitioning between plasma and erythrocytes, and between buffer and erythrocytes. Results obtained are compared with those from equilibrium dialysis or ultrafiltration techniques for amitriptyline, imipramine, quinidine, lidocaine, and propranolol. For each drug, the mean value of fu obtained with the erythrocyte partitioning procedure was not found to be significantly different from that determined by one of the two other classical techniques. The erythrocyte partitioning method lead to reproducible (mean C.V. = 6·25) and precise values of fu when compared to the other methods; its clinical application to lidocain gave results which agreed with those obtained by equilibrium dialysis.
Acute tolerance development to the diuretic effect of furosemide in the rat
Authors: Hammarlund Margareta , Paalzow Lennart K.
Published: October 2006

Furosemide was given to rats as five different i.v. bolus doses (2.5–100mg kg−1), or as an i.v. infusion to a steady‐state concentration in plasma of 14μg ml−1. The urinary furosemide excretion rate (ΔAe/Δt) and the diuretic effect (volume of urine) were measured. A parallel shift in the excretion—response curve was seen as a fivefold increase in (ΔAe/Δt)50 ((ΔAe/Δt) at half‐maximal effect) between the i.v. bolus doses from 2.5 to 40 mg kg−1. The slope factor did not change. During infusion, a decrease in efficiency to 20 per cent of the initial value was seen. These results are indicative of an acute tolerance development to the diuretic effect of furosemide. Some intrarenal feedback inhibition mechanism might be involved, as the extracellular fluid volume seems to be of great importance to the effect obtained. The resulting effect can be compared with the influence of a competitive antagonist.
Comparison of nonlinear pharmacokinetic parameters estimated from the sinusoidal perfusion and venous equilibrium models
Authors: Wagner John G.
Published: October 2006

It is shown that the intrinsic and steady‐state clearances and the values of Vm, and Km, of the Michaelis—Menten equation estimated via the sinusoidal perfusion model are different from the corresponding values estimated via the venous equilibration model. The liver blood flow rates estimated by two theories (from plasma data) are identical. The comparison was made using the single dose oral and intravenous and steady‐state oral plasma concentration—time data for verapamil in six subjects previously published.
Comparison of fitting methods for the analysis of plasma concentration‐time data resulting from constant rate intravenous infusion
Authors: Johnson Stephen L. , Mayersohn Michael
Published: October 2006

Plasma concentration‐time data resulting from constant rate intravenous infusion may be analysed in two ways:

Samples may be collected both during and after infusion and fit to an infusion model.

Samples may be collected after infusion is complete and the data may be fit as an i.v. bolus.

The purpose of this study was to contrast these two fitting procedures in terms of the accuracy of the parameter values obtained. Concentration‐time data were computer‐generated with the introduction of random error to simulate the disposition profiles of two model drugs. The results of these simulations indicate that satisfactory values for area‐dependent parameters may be obtained without fitting data during the infusion phase. The exception to this is the apparent steady‐state volume whose values become less accurate with longer infusion times. The parameters most affected by ignoring data points in the infusion phase are the central volume of distribution, and the coefficient and disposition rate constant associated with the initial, rapid phase of disposition. The equation which describes the entire concentration‐time profile provides the most accurate parameter estimates of the model equation. In addition, we also describe the influence of the fitting method on the intercompartmental transfer rate constants.
Comparative physiological disposition of some anthraquinone glycosides and aglycones
Authors: Moreau J. P. , Moreau S. , Skinner S.
Published: October 2006

The in vitro microbial degradation and the urinary excretion and biliary secretion in rats of two anthraquinone glycosides (sennosides A and B) and four aglycones (sennidins A and B, rhein, and danthron) were studied using a high performance liquid chromatographic system with gradient elution and amperometric detection. Microbial degradation of sennosides A and B occurred almost exclusively in the presence of mice caecum inoculae and was associated with the release of sennidins A and B. Rhein and danthron were indiscriminately metabolized by bacteria sampled from all regions of mice intestine, whereas sennidins lacked stability in biological media. The fraction of the dose administered orally to rats and recovered as aglycones or as glucuronides in bile and urine after 48 hours was five times greater for rhein (15 per cent) and danthron (13.4 per cent) than for sennosides A (1.8 per cent) and B (2.8 per cent) excreted or secreted as sennidins. These results support the concept that anthraquinone glycosides are less likely to enter the systemic circulation and, thus, are able to exert their laxative effect at lower doses than aglycones.
Confidence intervals for multiple‐dose concentrations in the one‐compartment open model with rapid intravenous injection
Authors: Karpinski K. F.
Published: October 2006

The parameters in a multiple‐dose compartmental model can be estimated from plasma concentration observations after a single dose of drug. These estimates can be used to obtain confidence intervals for the multiple‐dose concentrations. However, since the models are non‐linear functions of the parameters, no exact confidence interval procedures are available. In this paper a conservative interval estimation procedure1 is applied to the one‐compartment open model with rapid intravenous injection. Also, extended tables required in the estimation procedure are provided.
Selective incorporation of asialofetuin into hepatocyte of rat
Authors: Aramaki Yukihiko , Inaba Asaichi , Tsuchiya Seishi
Published: October 2006

The disposition of asialofetuin was studied in the rat. The radioactivity of 3H‐asialofetuin administered intravenously disappeared rapidly from the blood. Asialofetuin was specifically and rapidly incorporated into the liver, and had no affinity toward other tissues such as the lung, spleen, heart, and kidney. Asialofetuin accumulated in the lysosomal and microsomal fractions of the rat liver cells immediately after administration, shifted to the low dense fraction (cytosol fraction) with the elapsing of time, and was possibly digested by lysosomes. The elimination of 3H‐asialofetuin from the liver was fast and the degradates excreted into the bile and urine represented 90 per cent of the dose administered by 180 min following administration. It was suggested that asialofetuin functions as a carrier of drugs to the liver, especially to hepatocytes.
Allopurinol: A comparative study of the bioavailability and effect on plasma uric acid of two products in tablet form
Authors: Nissen Poul , Pedersen Linda
Published: October 2006

A comparative bioavailability study was carried out with two allopurinol products, i.e. Allopurinol tablets 100 mg, DAK, and Apurin® tablets 100 mg, Gea. Eleven healthy volunteers participated and were given a single dose of 200 mg of each product according to the cross‐over principle. The bioavailability was evaluated with respect to the maximum plasma concentration, the peak time, and the area under the plasma concentration‐time curve for allopurinol and the major metabolite oxipurinol. The elimination half‐life of oxipurinol was also estimated. None of the parameters showed statistically significant differences (p > 0.10) between the two products. Furthermore, the pharmacodynamic effect of the two products was examined with respect to the reduction of plasma uric acid within 24 hours after administration of 200 mg allopurinol. The two products did not differ significantly (p>0.10) in this respect. It is concluded that the two tablet products are bioequivalent.
Pharmacodynamics of acute intranasal administration of verapamil: Comparison with IV and oral administration
Authors: Arnold T. H. , Tackett R. L. , Vallner J. J.
Published: October 2006

The present study was conducted in order to examine the intranasal administration of verapamil and compare this route to oral and intravenous administration in a 3 way crossover protocol in five dogs. Unanesthetized, adult mongrel dogs were given verapamil intravenously (0.5 mg/kg), orally (2.5 mg/kg) and intranasally (0.75 mg/kg) with at least a 3–4 day washout period between each administration. Blood samples were collected over a 10 hour period and analyzed for verapamil using HPLC with fluorescence detection. A lead II ECG was monitored to determine the effects of verapamil on heart rate and P‐R interval. Following intravenous administration, verapamil was distributed according to a two compartment model. Bioavailability (corrected for dose and elimination rate constant) following intranasal administration (36% ± 7%) was approximately 3 fold that after oral administration (13% ± 3%). Absorption from the nasal cavity appeared instantaneous compared to an absorption half‐life of 50 ± 6 min after oral administration. All three routes of administration resulted in significant increases in heart rate and increases in the P‐R interval. Maximal P‐R interval prolongation occurred after peak plasma concentrations of verapamil. The results of this study suggest that the intranasal route is a viable alternative route of administration for verapamil.
Acetylsalicylic acid metabolites in blood and urine after plain and enteric‐coated tablets
Authors: Montgomery P. R. , Sitar D. S.
Published: October 2006

Acetylsalicylic acid (ASA) was administered orally as a single dose to 7 healthy male volunteers as plain or enteric‐coated (EntrophenR) tablets using a crossover design. Blood and urine samples were collected and analysed for ASA metabolites by high performance liquid chromatography. Labile and stable glucuronide conjugates of salicylic acid (SA) were measured in urine after differential hydrolysis with glucuronidase. Plasma kinetic parameters for the ASA metabolites SA and salicyluric acid were not different for the 2 formulations, apart from the delayed appearance after the enteric‐coated tablets. Total urinary recovery, and recovery of salicyluric acid and the two SA glucuronides were not different, thus confirming the equivalent bioavailability and metabolite profile of the 2 ASA formulations.
Influence of dioctyl sodium sulfosuccinate on the absorption of tetracycline
Authors: Shah Vinod P. , Hunt John P. , Fairweather William R. , Prasad Vadlamani K. , Knapp Gene
Published: October 2006

A pilot bioavailability study was carried out to evaluate the drug interaction and influence of dioctyl sodium sulfosuccinate (DS) on the absorption/bioavailability of tetracycline. Three tetracycline products—a fast dissolving capsule, a slow dissolving capsule and a suspension, were used in the study. DS was administered (a) 30 minutes before tetracycline administration; and (b) on −3, −2 and −1 day in the evening before tetracyline administration. Frequent urine samples were collected up to 48 hours and analyzed by a microbiological method. Although not statistically significant in this small study, the results suggest that there is a reduction in tetracycline bioavailability due to DS. The indiscriminate use of surface active agents to increase the dissolution rate of solid oral dosage forms in the belief that the resulting increased dissolution improves product bioavailability must be questioned.
Relationship between plasma propranolol concentration and dose in young, healthy volunteers
Authors: Dey Mike , Brisson Jerry , Davis Gloria , Enever Robin , Pray Kathryn , Zaim Beyhan , Dvornik Dushan
Published: October 2006

The relationship between dose and bioavailability of propranolol was determined in 12 healthy male subjects. The doses employed were 10, 40, 80 or 160 mg of propanolol HCI given three times daily for 4 days. Daily minimum plasma levels showed that there was no accumulation of the drug. In all subjects, non‐linear relationships were observed between peak plasma level, or area under the plasma concentration‐time curve, and dose. The between subject variation of these parameters was not dose related.
Use of a limited physiologic model to explain target organ toxicity of bupivacaine as a function of route of administration
Authors: Denson Donald D. , Thompson Gary A. , Coyle Dennis E.
Published: October 2006

A physiologic model to describe bupivacaine uptake by and elimination from brain and heart was developed. Preliminary validation of the model was accomplished by comparing concentration data predicted by the model with those determined in rabbits. The model was modified to examine similarities and differences following intravenous and epidural administration of 150 mg of bupivacaine in humans. Simulations illustrated why rapid cardiovascular and central nervous system toxicity occurs following intravenous administration and is absent when an identical dose is administered epidurally. A slow continuous intravenous infusion of bupivacaine was simulated to examine the possibility that brain and heart concentrations would continue to accumulate reaching toxic concentrations in the absence of blood concentrations associated with bupivacaine toxicity.
The disposition of pyrimethamine base and pyrimethamine pamoate in the mouse: Effect of route of administration
Authors: Coleman M. D. , Mihaly G. W. , Edwards G. , Howells R. E. , Breckenridge A. M.
Published: October 2006

We have investigated the plasma pharmacokinetics and mass fate in mice, of pyrimethamine administered as either the base or as the poorly soluble pamoate salt, in each case by the intraperitoneal (i.p.) and subcutanous (s.c.) routes. Following the administration of pyrimethamine base (i.p. and s.c.) and pyrimethamine pamoate (i.p.), maximum measured plasma levels of pyrimethamine were attained within 1 h, before declining monoexponentially. There was no significant difference between these three groups in the clearance (0.29 ± 0.05, 0.30 ± 0.03, 0.26 ± 0.05 ml min−1), elimination half‐life (4.5 ± 0.5, 4.8 ± 0.8, 4.9 ± 0.5 h) and AUC (19.4 ± 4.4, 17.3 ± 2.2, 21.1 ± 4.4 μg. h ml−1).

By contrast, after s.c. dosage of pyrimethamine pamoate, drug absorption was significantly delayed, maximum plasma levels being reached after 4h, these levels being approximately one‐third of those in the other three groups. Absorption was however complete, as the values for AUC and clearance were not significantly different from the other groups.

The pattern of faecal and urinary elimination of 14C radioactivity was unaffected by either dose site or formulation of pyrimethamine. The majority of the dose (44.5–64.2 per cent) was eliminated in the faeces suggesting extensive biliary excretion. Localization of 14C radioactivity in the major organs was negligible in all groups. Following each dose, between 85 and 98 per cent of the dose was accounted for.

These studies indicate that of the four treatment groups only pyrimethamine pamoate on s.c. administration demonstrates a sustained release action from the dose site. This effect is not accompanied by any differences in AUC, clearance, and rate of elimination, when compared with the base given i.p. and s.c., or the pamoate salt given i.p., the latter groups displaying no slow release characteristics.
Pharmacokinetics and bioavailability of the anti‐emetic agent bromopride
Authors: Brodie R. R. , Chasseaud L. F. , Darragh A. , Lambe R. F. , Rooney L. , Taylor T.
Published: October 2006

The pharmacokinetics of bromopride, an anti‐emetic agent chemically related to metoclopramide, has been investigated in normal human subjects. After intravenous bolus doses of 10 mg, a one‐compartment open model appeared adequate to describe the plasma drug concentration data. The systemic clearance of bromopride was 899 ml min−1 ± 22 per cent CV, the volume of distribution was 2151 ± 16 per cent CV, and the elimination half‐life was 2.9h ± 21 per cent CV. Over a wide drug concentration range of up to 650ng ml−1, bromopride was only 40 per cent bound to plasma proteins. The systemic availability of orally and intramuscularly administered solution doses of 20 mg of bromopride was 54 per cent and 78 per cent, respectively. Formulation of bromopride as the solid material in capsules delayed absorption but did not affect the extent of drug bioavailability. The pharmacokinetics of bromopride appeared similar to that of metoclopramide. No evidence for non‐linear kinetics was found when bromopride was administered orally in the dose range 10–30 mg: after single oral doses of 10, 20, and 30 mg, peak mean plasma drug concentrations were 20 ng ml−1 ± 32 per cent CV, 38 ng ml−1 ± 16 per cent CV, and 64 ng ml−1 ± 23 per cent CV, respectively.
Pharmacokinetics of orally administered hexobarbital in plasma and saliva of healthy subjects
Authors: Van Der Graaff M. , Vermeulen N. P. E. , Heij P. , Boeijinga J. K. , Breimer D. D.
Published: October 2006

Hexobarbital (HB) concentrations were determined in plasma and saliva of 8 healthy subjects, following oral administration of 500 mg HB‐Na. Mean plasma half‐lives were 3.2 ± 0.1 h, and salivary half‐lives 3.3 ± 0.2 h. Mean plasma clearance was 22.9 ± 2.3 1h−1. There was a linear relationship between HB concentrations in saliva and plasma (r = 0.92). Mean salivary levels were 34 per cent of plasma levels. Salivary pH was constant throughout the experiment, 7.06 ± 0.09. There was an inconsistent tendency of the saliva over plasma ratios to increase as a function of time. The percentage of protein binding calculated from saliva over plasma ratios was in reasonable agreement with in vitro data of equilibrium dialysis, 64.1 ± 2.6 per cent and 65.9 ± 0.8 per cent, repectively. The experiment was repeated in 4 subjects, and considerable intraindividual differences were shown to exist in saliva over plasma ratio, half‐lives, and protein binding.

It was concluded that HB elimination half‐lives can relatively accurately be determined from salivary concentrations. Oral plasma clearance can only be estimated if the individual saliva over plasma ratios are known; this would require the taking of at least one blood sample during the experiment. When employing HB as a model substrate for drug metabolizing enzyme activity in vivo, the determination of its pharmacokinetic parameters, particularly oral plasma clearance as a reflection of cytochrome P‐450 activity, cannot be achieved by taking saliva samples only.
Rotary pursuit, a measure of human performance, and plasma concentrations of promethazine
Authors: Kotzan J. A. , Honigberg I. L. , Francisco G. E. , Zaman R. , Stewart J. T. , Brown W. J.
Published: October 2006

Promethazine in doses of 50 mg has demonstrated detrimental effects upon the performance of visual tasks. The purpose of the study was to examine the relationship between the blood concentration levels of promethazine and two human performance tasks. Fifteen paid healthy male volunteers completed a randomized five‐way crossover design which included a 25 mg and 50 mg dose of the innovator dosage form, a 50 mg dose of a generic dosage form, a 50 mg solution dosage form, and a placebo. Serial blood samples were obtained in addition to performance measures of rotary pursuit and a simple force choice reaction time. Analysis of the forced choice reaction depicted a mild relationship with the blood concentration levels of promethazine. However, the measures of rotary pursuit, a more sensitive determinant of human motor performance, proved to be more related to both the promethazine blood concentration and the inherent learning which was confounded in the experiment. The degree of impaired pursuit performance and reaction time differences could be defined in terms of a linear relationship to the promethazine concentration.
The effect of food and time of administration on the absorption of diethylamine chromocarbe
Authors: Aiache J.‐M. , Faurie M. , Sibaud Y. , Kaftelip J.‐P. , Aiache S.
Published: October 2006

In order to evaluate the influence of food and time of administration on the absorption of diethylamine chromocarbe, a bioavailability study was performed in 8 volunteers by using a new method of plasmatic drug evaluation.

The results obtained indicate that lunch has little effect on diethylamine chromocarbe absorption in comparison with the administration 0.5 h before breakfast. The bioavailability parameters Cmax, tmax, and AUC are not statistically different and the two methods of administration can be considered as bioequivalent.

The absorption of diethylamine chromocarbe seems to be reduced when the drug is administered before dinner. This delay on absorption may be due to circadian rhythm of tractus gastrointestinal absorption or to the reduction of physiological activity of volunteers.
Importance of analytical methods in pharmacokinetic and drug metabolism studies
Authors: Hirtz J.
Published: October 2006

Pharmacokinetic and drug metabolism studies first request that good analytical data are available. The various methods that permit unchanged drugs and their metabolites to be separated, identified and quantitatively assayed are briefly reviewed. The present importance of gas chromatography/mass spectrometry is emphasized, as well as the limits of immunological assays. The sensitivity of the analytical assay has a direct impact on the validity of the pharmacokinetic model which is built up from plasma concentration data. The precision and accuracy of the assay is also critical, and it is not always easily estimated. A new significant parameter is the speed of analysis, and the resulting massive production of analytical data. New drugs coming from biotechnology, and new dosage forms, like targeted drugs, will create new analytical problems in the future. They will probably call for the development of new biological or pharmacological assay procedures, in addition to the physicochemical means of analysis.
Plasma concentrations and relative bioavailability of naftidrofuryl from different salt forms
Authors: Walmsley L. M. , Taylor T. , Wilkinson P. A. , Brodie R. R. , Chasseaud L. F. , Alun‐Jones V. , Hunter J. O.
Published: October 2006

The relative bioavailability of the vasodilator naftidrofuryl from formulations containing its oxalate or citrate salt has been estimated using a specific HPLC assay, and a less specific fluorimetric assay, to measure plasma drug concentrations. The conclusions of the study were the same irrespective of the assay employed. The relative rate, but not the extent, of bioavailability of naftidrofuryl from the citrate salt (peak 1096 ng ml−1 at 0·76 h) was marginally greater (p = 0·003) than that from the oxalate salt (peak 922ng ml−1 at 0·94 h). The degree of intersubject variability was similar after administration of either salt form. The mean half‐life of naftidrofuryl was 1·8 h and its mean residence time was 2·5 h.
Ceforanide pharmacokinetics in haemodialysis: The effect of ultrafiltration
Authors: Lanao José M. , De Prada Consuelo R. , Dominguez‐Gil Alfonso , Tabernero José M. , Martín Jesús , Gómez Juan R.
Published: October 2006

The kinetics of ceforanide in plasma and dialysate was studied in 8 patients with terminal renal impairment after undergoing haemodialysis sessions lasting between 4 and 5 h. All patients received a single i.v. dose of 15 mg kg−1 of the drug at the start of the session. The dialysers used in this study were Spiraflow capillar 1·3 m2, Travenol plates 1·4 m2, and PAN plates. Blood flow ranged between 200 and 300 ml min−1 and dialysate flow between 500–650 ml min−1. Plasma ceforanide levels were measured at the input and output of the dialyser and the antibiotic levels in dialysate were determined coinciding with the withdrawal times of the blood samples. A microbiologic plate diffusion method was used to determine the antibiotic concentrations.

The mean values of some pharmacokinetic parameters of ceforanide calculated with a non‐linear regression program from the data obtained from arterial blood were the following: α (h−1) = 4·14 ± 1·32; β (h−1) = 0·26 ± 0·07; t1/2 β (h) = 2·82 ± 0·82; Vdss (1) = 10·24 ± 2·14.

From the relationships between the antibiotic concentrations at the input and output of the dialyser it was possible to calculate an extraction coeffficient of 0·11 ± 0·06. The dialysis clearance of ceforanide was calculated from the determination of the extraction coefficient and from the measuring of antibiotic in dialysate, though different results were obtained with the two methods. Dialysis clearance calculated from the extraction coefficient showed a mean value of 18·68 ± 12·16 ml min−1, significantly lower (p < 0·01) than that established by analysis of the antibiotic in dialysate, which was 41·55 ± 15·83 ml min−. These differences may be attributed to problems related to the determination of blood flow and to the ultrafiltration capacity of the dialysis membranes. A linear relationship was established between the percentage error in the observed and predicted extraction coefficients and the ultrafiltration rate. The results obtained suggest that the simultaneous measurement of the antibiotic in plasma and dialyate is the most suitable method for predicting the dialysis clearance of the drug. The amount of antibiotic extracted over a 4‐hour dialysis session proved to be equal to 57·85 ± 15·62 per cent of the dose administered.
Renal and non‐renal clearances of iothalamate
Authors: Prueksaritanont Thomayant , Lui Chung Y. , Lee Myung G. , Chiou Win L.
Published: October 2006

An evaluation of the literature indicated that certain aspects of the disposition kinetics of iothalamate, important to the accurate determination of glomerular filtration rate in dogs and humans, remain to be resolved. The simultaneous clearances of iothalamate and inulin in 5 dogs were determined at three steady‐state iothalamate plasma levels (2, 10, and 40μg ml−1) following various rates of intravenous infusion. The iothalamate clearances, both renal and non‐renal, were concentration‐independent. The overall mean non‐renal clearance was 18 per cent (ranging from 9 to 25 per cent) of its plasma clearance. The mean iothalamate/inulin renal clearance ratio was about 0·84 with individual values ranging from 0·72 to 0·95. The significant (4–26 per cent) plasma protein binding of iothalamate in these dogs was the main reason for the lower‐than‐unity clearance ratios obtained. The literature indicates the existence of up to 25 per cent of non‐renal elimination in humans with normal renal function; this is comparable to the present results obtained with dogs but contrary to the assumption, sometimes reported in the literature that non‐renal elimination is essentially absent in humans. Binding of iothalamate to plasma proteins from humans was not found in the present study. The above results suggest that for accurate glomerular filtration rate determination in humans and dogs, especially for those with renal impairment, renal clearance rather than plasma clearance should be used, and in the case of dogs it should also be corrected for plasma protein binding. Iothalamate in plasma and urine was analysed by a simple, micro high‐performance liquid chromatographic method with UV detection.
Pharmacokinetics of insulin following intravenous and subcutaneous administration in canines
Authors: Ravis William R. , Comerci Carol , Ganjam Ventateseshu K.
Published: October 2006

Studies were conducted to examine the absorption and disposition kinetics of insulin in dogs following intravenous (IV) and subcutaneous (SC) administration of commercial preparations. After IV and SC dosing, the plasma levels were described by models which considered basal insulin level contributions. Intersubject variation in the disposition kinetics was small with half‐lives of 0.52 ± 0.05 h and total body clearances of 16.21 ± 2.08ml min−1kg−1. Calculated insulin plasma secretion rates in the canines were 14.4 ± 3.3 mUh−1kg−1. Following SC injection of regular insulin, the rate and extent of absorption were noted to be quite variable. The absorption process appeared first‐order with half‐life values of 2.3 ± 1.3 h and extents of absorption of 78 ± 15 per cent with a range of 55–101 per cent. Insulin absorption from SC NPH preparations was evaluated as being composed of two zero‐order release phases, a rapid and a slow release phase. With a dose of 1.65 U kg−1, the rapid release phase had an average duration of 1.5 h and a rate of 580 ± 269 mU h−1(4.2 per cent of dose) while the slow phase had a zero‐order rate of 237 ± 92mU h−1which continued beyond 12h. The extent of absorption from the NPH preparation was 23.6 ± 5.1 per cent and was significantly lower than that for the regular injection.
Time‐dependent inhibition of theophylline elimination by erythromycin stearate
Authors: Adebayo G. I. , Adewumi M. O. , Mabadeje A. F. B.
Published: October 2006

The effect of erythromycin stearate at a dose of 1 g daily on theophylline disposition was studied in six healthy adult males. The mean value of 5·46 h for the theophylline half‐life after 48 h pretreatment with erythromycin stearate was not significantly different from the control value of 5·24h. The half‐life value of 8·48 h after a 1‐week course of the antibiotic, however, represented a significant increase (p < 0·005). Theophylline disposition 1 week after the last dose of the antibiotic was not significantly different from the control. It is suggested that therapeutic doses of erythromycin stearate for a week or more could impair the disposition of concurrently administered theophylline. The impairment however, is reversible, being absent a week after the last antibiotic dose.
Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of furosemide
Authors: Lee Myung G. , Li Tun , Chiou Win L.
Published: October 2006

The pharmacokinetics and pharmacodynamics of furosemide were evaluated after intravenous administration of the same total dose of furosemide in different lengths of infusion time (10s, 30 min, 2h, and 8h) to 6 dogs. The fluid loss in urine was immediately replaced volume for volume with intravenous infusion of Lactated Ringer's solution. The pharmacokinetic parameters such as per cent of the dose excreted in urine, total body and renal clearances, and terminal half‐life were not significantly different with four different infusion times. The volume of distribution at steady state and mean residence time based on venous data, on the other hand, appeared to increase with increasing infusion time. The mean values for Vss were 0·334, 0·478, 0·499, and 0·708 1 kg−1 for 10s, 30 min, 2h, and 8h of infusion, respectively, and the corresponding values for MRT were 17·5, 22·2, 24·8, and 38·1 min. The diuretic effects (urine output and urinary excretion of sodium) were generally found to increase with increasing infusion times; the total mean 24h urine outputs were 1102, 1464, 2190, and 3470 ml for 10 s, 30 min, 2h, and 8h of infusion, respectively, and the corresponding values for sodium excretion were 170, 175, 272, and 440 mmol. Furosemide plasma concentrations and hourly urinary excretion rates of furosemide, sodium, and potassium during the apparent steady state (between 2 and 8h) in the 8h infusion study were fairly constant.
Correlation between inhibitory effect on platelet aggregation and disposition of sulfinpyrazone and its metabolites in rabbits. Part II: Multiple dose study
Authors: Kuo Be‐Sheng , Ritschel Wolfgang A.
Published: October 2006

In a crossover study rabbits were given perorally sulfinpyrazone (SO) and the sulfide metabolite (S) every 24h for 5 days on separate occasions and inhibition of aggregation was measured. The results showed: (1) the dosage regimen is effective if the minimum effective concentration of S is defined to be between 0.5–1.0μg ml−1 and (2) the repeated dosing did not cause changes in disposition kinetics except that the terminal half‐life of S was reduced after dosing with S. No significant accumulations in trough concentration and inhibition of aggregation were observed. The results obtained in this study could provide some useful information for design of dosage regimen and blood level monitoring for humans.
Sulfamethazine absorption and disposition: Effect of surgical procedures for gastroduodenal ulcers
Authors: Calvo Rosario , Sarabia Sebastian , Carlos Raimundo , Souich Patrick Du
Published: October 2006

This study was designed to determine whether the surgical procedures for gastroduodenal ulcers influence sulfamethazine (SMZ) absorption and disposition. Prior to and on the average 79 days after surgery, eight patients received 10mg kg−1 of sulfamethazine orally. Blood samles were obtained at regular intervals over 24h and urine was collected for 48h. Vagotomy with pyloroplasty or with gastrojejunostomy had no effect on SMZ kinetics. Vagotomy with partial gastrectomy decreased the SMZ plasma peak concentrations from 43.9 ± 7.1 (mean ± SEM) to 17.2 ± 5.2 μg ml−1 (p < 0.05) and increased the time required to reach this peak from 2.6 ± 0.8 to 9.8 ± 2.8 h (p < 0.05). SMZ rate constant of absorption decreased only slightly (1.22 ± 0.45 to 0.24 ± 0.07 h−1) and SMZ bioavailability was not affected at all. In two (out of four) patients, SMZ volume of distribution and total body clearance increased, as reflected in the 41 per cent decrease in the mean area under the SMZ plasma concentration–time curve. No changes were detected in SMZ protein binding. Computer simulations indicated that in some subjects SMZ plasma concentrations at steady state could be 76 per cent lower following vagotomy with partial gastrectomy than before surgery. It was concluded that vagotomy and antrectomy with a gastroduodenostomy or Billroth I reconstruction decreased the rate of SMZ absorption and only in some subjects increased the SMZ volume of distribution and rate of elimination. The possible mechanisms involved in these reported kinetic changes are discussed.