bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toward a quantitative approach for the prediction of the fraction of dose absorbed using the absorption potential concept
Authors: Macheras Panayotis E. , Symillides Mira Y. 
Published: October 2006

AbstractAn equation based on the absorption potential concept was developed. This enabled us to establish an approach for the quantitative prediction of the fraction of dose absorbed. Classification of drugs into three broad categories, according to their absorption potential values in relation to the fraction of dose absorbed, was attempted. The new approach was tested using literature data with very good results.
Physiologically based pharmacokinetic model for the renal clearance of iodopyracet and the interaction with probenecid in the dog
Authors: Russel Frans G. M. , Wouterse Alfons C. , Van Ginneken Cees A. M. 
Published: October 2006

AbstractPlasma kinetics and renal excretion of iodopyracet (3·0 g, adminstered i.v.) with and without concomitant administration of probenecid were studied in the beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid. A physiologically based kidney model is proposed comprising all the functional characteristics of the kidney that determine the excretion of iodopyracet, i.e. renal plasma flow, urine flow, protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. Renal clearance of iodopyracet is characterized by supply‐limited elimination at low plasma concentrations and capacity‐limited elimination at high plasma levels. The interactioin with probenecid could be adequately described with the model by competitive inhibition of the carrier‐mediated uptake of iodopyracet into the tubular cells. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of iodopyracet within the cells, which was clearly diminished in the presence of probenecid.
Primaquine disposition in the isolated perfused rat liver: Effect of mefloquine induced bile flow reduction
Authors: Coleman Michael D. , Fleckenstein Lawrence , Heiffer Melvin H. 
Published: October 2006

AbstractThe disposition of primaquine (0·75 mg, 5 μCi) has been investigated in the isolated perfused rat liver (IPRL) preparation alone and concurrently with mefloquine. In both groups, primaquine concentrations declined exponentially. There were no significant differences between the respective groups in the half‐lives (2·5 ± 1·5, 2·2 ± 1·1 h), AUCs (0·43 ± 0·14, 0·372 ± 0·096 μg·h ml−1), clearances (19·0 ± 5·4, 21·1 ± 4·2 ml h−1), and apparent volume of distribution (78·9 ± 28·1, 76·2 ± 31·7 ml). In the presence of mefloquine, total bile production was significantly reduced (1244·5 ± 317·1 μl) compared with primaquine alone (1621·5 ± 174·2 μl). Hence, although significantly less radioactivity ([3H]) was eliminated in bile in the presence of mefloquine (30·0 ± 7·9 per cent versus 39·9 ± 3·6 per cent) there was no significant difference between the groups in [3H]/μl bile eliminated. Significantly more [3H] was recovered from the livers of the mefloquine/primaquine group. This was underlined by the significantly greater proportions of [3H] recovered from the 10000 g pellet, 10000 g supernatant and 105000 g supernatant in the presence of mefloquine compared with primaquine alone. Hence, it appears mefloquine had little or no direct action or primaquine metabolism, but significantly reduced bile production.
Pharmacokinetics and pharmacodynamics of physostigmine in the rat after oral administration
Authors: Somani Satu M. 
Published: October 2006

AbstractThe distribution, metabolism, and pharmacokinetics of physostigmine (Phy) and the time course of butyrylcholinesterase (BuChE) in plasma and cholinesterase (ChE) activity in brain and muscle and their relationship to Phy concentration were described after oral administration of 3H‐Phy (650 μg kg−1) to rats. Physostigmine concentration vs time data was analyzed by nonlinear computer fitting program using one‐compartment model. The absorption rate constant (ka) and elimination rate constant (ke) were found to be 0·1 ± 0·07 min−1 and 0·036 ± 0·024 min−1, respectively. Cpmax and tmax were 3·3 ng ml−1 and 16 min. The clearance (Cl) was found to be 80·9 ml min−1 kg−1. Half‐life of Phy in brain, muscle, and liver were 33·4min, 22·5, and 28 min, respectively. The bioavailability (F) was calculated to be 0·02 and the extraction ratio was found to be 0·98 indicating the ‘first pass’ effect. Butyrylcholinesterase activity in plasma was 76 per cent at 15 min and this activity did not change significantly up to 120 min. However, Phy concentration in plasma was very low; 2·89 ng ml−1 at 15 min and declined to 0.71 ng ml−1 at 90 min. Physostigmine concentration in brain peaked at 22 min to 2·85 ± 1·09 ng g−1 and declined to 0·33 ± 0·11 ng g−1 at 60 min. Cholinesterase activity in brain was 96 per cent, 82 per cent and 89 per cent at 10, 45, and 120 min, respectively. Physostigmine concentration in muscle was very low and the ChE activity in the muscle was 66·4 per cent of control at 45 min. The time course of Phy metabolism indicated that at 5 min most of the RA in the tissues was due to metabolites accounting for 94·6 per cent in plasma, 90 per cent in liver, 79·8 per cent in brain and 86·3 per cent in muscle. M1 appeared to be the major metabolite followed by eseroline. The results showed extremely low concentrations of Phy (200 times less in plasma and 350 times less in brain) after oral administration compared to our previous studies with the same dose after i.m. administration.
Ocular absorption of benzydamine by the rabbit
Authors: Catanese B. , Valeri P. , Lagana A. , Curini L. 
Published: October 2006

AbstractAn aqueous solution of 0·15 per cent benzydamine hydrochloride, a non‐steroidal anti‐inflammatory drug, was applied to the rabbit eye. Following topical application to the cornea, the drug was soon detected in the aqueous fluid of the treated eye, whereas the plasma levels were negligible. The possibility that benzydamine can inhibit inflammatory processes in the eye without the risk of side‐effects is discussed.
Pharmacokinetic interactions between arbaprostil and aspirin in humans
Authors: Hsyu Poe‐Hirr , Cox Jeffrey W. , Pullen Robert H. , Gee Winnie L. , Euler Arthur R. 
Published: October 2006

AbstractArbaprostil is an orally active prostaglandin E2 analogue. It has been developed as a drug to treat ulcers induced by non‐steroidal anti‐inflammatory drugs. In this study, pharmacokinetic interactions between arbaprostil and aspirin were examined in humans after chronic doses of both drugs. Subjects received either arbaprostil (50 μg), asprin (975 mg) or arbaprostil (50 μg) and aspirin (975 mg) four times a day for 6 days and one dose on 7th day. Blood and urine samples were collected after the last dose for 6 h. Pharmacokinetic parameters of arbaprostil, aspirin, and Salicylate were determined. Coadministration of arbaprostil significantly lowered the area under curve (5·09 ± 0·32 μg hml−1vs 5·78 ± 0·29 μg hml−1, mean ± SE, p < 0·05) and time (0·45 ± 0·07 h vs 0·70 ± 0·12 h, p < 0·05) to reach maximal plasma concentration of aspirin (acetylsalicylate). The pharmacokinetics of salicylate were not changed by arbaprostil, nor were the pharmacokinetics of arbaprostil affected by aspirin. Coadministration of these two drugs did not appear to potentiate the side‐effects of either drug. The results suggest that arbaprostil and aspirin may be administered together without clinically significant changes in pharmacokinetics or adverse side‐effects.
Pharmacokinetic interaction between diltiazem and amiodarone in the dog
Authors: David Joseph Ben , Bialer Meir 
Published: October 2006

AbstractThe pharmacokinetic interaction between diltiazem and amiodarone was investigated in dogs. In the presence of amiodarone, diltiazem's AUC values were significantly increased and its total body clearance and volume of distribution at steady‐state significantly decreased. This study indicates that cardiac patients on combined diltiazem‐amiodarone therapy may indeed be in a high risk situation in regards to the unexpectedly high blood levels of diltiazem induced: with the ultimate introduction of such side‐effects as (1) the lowering of blood pressure, (2) A/V block, and (3) sinus node depression. Such cases would require immediate dosage adjustment.Assuming that the data obtained in this study can be extrapolated to humans, a patient's physiological parameters should be monitored at periodic intervals and, more importantly, the patient should report the first sign of any untoward effect.
Slow release theophylline disposition and effect in elderly patients with chronic obstructive lung disease: Influence of dose formulation and institutionalization
Authors: Montgomery Patrick R. , Aoki Fred Y. , Mitenko Paul A. , Vanzieleghem Michael , Sitar Daniel S. 
Published: October 2006

AbstractWe studied the steady‐state disposition of slow release theophylline tablets and granules in 12 institutionalized (I) and 12 community‐dwelling (C) elderly patients with fixed chronic obstructive lung disease. Design was open label with random order crossover; each formulation was given 5 min before food every 12h for 7 days. Age (median 70y, range 55–88), sex, smoking status, and baseline lung function off drug were similar. Trough plasma concentration (Cp) was higher with the tablets as was the area under the Cp vs time curve: 134 (74–252) vs 121 (75–197) mghl−1;p=0·028. The standard deviation of Cp over one dose interval was lower with the granules. FEV1·0 was slightly improved over baseline. Dose required to reach target Cp was higher in the institutionalized group (12·6 vs 8·6mg kg−1 day−1; p=0·003) as was apparent clearance; I:94 (43–148) ml hr−1 kg−1 vs C:68 (34–163); p=0·003. Although biovailability was slightly reduced for the granules, fluctuations of Cp was less, and we failed to find a food effect that was clinically important in geriatric subjects.
Prediction of steady state bioequivalence relationships using single dose data II‐nonlinear kinetics
Authors: Jackson André J. 
Published: October 2006

AbstractTwo nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma‐concentration time curve values from 0 to infinity (AUC 0–∞) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing.The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0–∞ showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0–∞ from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.
The effect of domperidone on theophylline disposition in the rat
Authors: Bawazir S. A. , Al‐Hassan M. I. , Matar K. M. , Tekle A. 
Published: October 2006

AbstractThe effect of domperidone (2 mg kg−1) on the pharmacokinetics of a single oral dose of theophylline (25 mg kg−1) was studied in the rat. Theophylline concentrations were measured serially for 12 h using an HPLC technique. Domperidone did not have any significant effect on any of the four parameters studied: peak plasma levels (Cpmax), the time these were attained (tmax), elimination half‐life (t1/2) and area under the plasma concentration‐time curve (AUC). Our data preliminarily suggests that domperidone may be safely coadministered with theophylline but clearly further studies in patients or relevant animal models of gastric motility disturbances are needed to reliably rule out any potential interaction between these agents.
Lack of effect of co‐trimoxazole on the pharmacokinetics of orally administered theophylline
Authors: Lo K. F. , Nation R. L. , Sansom L. N. 
Published: October 2006

AbstractEight healthy, male subjects participated in a balanced randomized crossover study to investigate the effect of a course of co‐trimoxazole (CT; combination of sulphamethoxazole 800 mg and trimethoprim 160 mg, twice daily for 5 days) on the pharmacokinetics and urinary metabolite profile of an orally administered dose of theophylline (TH). There were no significant differences (p> 0·05) between the control and treatment phases with respect to any of the following pharmacokinetic parameters of TH: area under the plasma total TH concentration‐time curve; fraction unbound in plasma; area under the plasma unbound TH concentration‐time curve; terminal half‐life; apparent volume of distribution; apparent total plasma clearance and renal clearance. The urinary recoveries of 1‐methyluric acid, 1,3‐dimethyluric acid and of theophylline were not significantly different (p> 0·05) between the two study phases. There was a significant difference (p< 0·05), however, in the urinary recovery of 3‐methylxanthine (11·3 ± 2·6 per cent TH alone versus 13·9 ± 3·6 per cent TH‐CT) and in the total urinary recovery of TH and its metabolites (76·5 ± 8·2 per cent versus 85·3 ± 7·0 per cent), the latter finding suggesting that CT may have caused a small increase in the extent of TH absorption. The results of the study indicated that CT did not inhibit the biotransformation of TH.
Pharmacokinetic interaction between flurbiprofen and antacids in healthy volunteers
Authors: Caillé G. , du Souich P. , Vézina M. , Pollock S. R. , Stalker D. J. 
Published: October 2006

AbstractGastrointestinal distress resulting from drug intake is often remedied by administering the drug with antacids. However, antacids have been shown to modify the absorption and excretion of many drugs. This study was designed to delineate the effects of aluminium and magnesium hydroxide antacid suspension (Maalox) on the pharmacokinetics of flurbiprofen. Since this drug is often used in the elderly, not only young healthy but also geriatric healthy male volunteers participated in the study. A group of twelve young and a group of seven geriatric volunteers received, in a crossover design, a single oral dose of 100 mg of flurbiprofen with and without Maalox. A non‐stereospecific assay was used to determine the total (R+S enantiomers) of flurbiprofen in plasma. The relative pharmacokinetic parameters of total flurbiprofen determined from plasma samples were Cmax, tmax,Kel, t1/2, and AUC∞. The results indicate that the co‐administration of Maalox with flurbiprofen had no effect on the rate and extent of total flurbiprofen absorption in young volunteers. In geriatric volunteers, the results indicate no effect of the antacid on the extent of drug absorption. There was a trend for lower plasma concentrations of total flurbiprofen with antacid in the geriatric group and hence a reduction in rate of flurbiprofen absorption although differences were not significant. The study also included a steady state determination of the influence of antacid administration on flurbiprofen pharmacokinetics. The group of young volunteers received, from Day 3 to Day 8, 100 mg of flurbiprofen every 12 h with and without Maalox. Steady state pharmacokinetics were similar to those after single administration: the antacid had no effect on either the rate or the extent of total flurbiprofen absorption.
Absence of effect of food on alprazolam absorption from sustained release tablets
Authors: Eller Mark G. , Della‐Coletta Andrew A 
Published: October 2006

AbstractThis study examined the effect of food on alprazolam absorption from a mixed polymeric matrix sustained release (SR) tablet in 21 healthy adults. Each subject received each of three treatments according to a crossover design: 1 mg alprazolam SR tablet while fasting; 1 mg alprazolam SR tablet immediately after a standardized breakfast; 1 mg alprazolam conventional tablet while fasting. The breakfast contained approximately 33 g protein, 55 g fat, and 58 g carbohydrate (850 calories). Serial blood samples were obtained and plasma alprazolam levels determined by HPLC. Results indicate that the SR tablet was minimally affected by food. Relative bioavaiabilities of the SR tablet while fasting and with food were 100 per cent and 97 per cent, respectively. Although statistically significant, differences in mean Cmax values between SR tablets administered with and without food were small (12 per cent increase with food). Rates of absorption as measured by mean tmax values were also nearly the same: 7·2 h while fasting and 7·0 h with food. Absorption was relatively uniform with the SR tablets. Coefficients of variation for Cmax, tmax, and AUC were somewhat smaller with the SR tablet than with the conventional tablet.
Absorption of doxycycline from a controlled release pellet formulation: The influence of food on bioavailability
Authors: Williams Desmond B. , O'Reilly William J. , Boehm Garth , Story Michael. J. 
Published: October 2006

AbstractA three‐way crossover study was performed to compare the bioavailability of a new pelletised doxycycline product administered either with food or without food and a reference product taken without food.Four different methods were used to calculate pharmacokinetic parameters from the data. The sums of squares, Akaike's Information Criterion (AIC), and the ranges for the parameters obtained were used for comparison. Good fits to the data were obtained when all four methods were used, each with a lag time. The two compartment open model was the most efficient method for describing the data. The one compartment open model was the least efficient, particularly with respect to predicting the peak concentration of doxycycline in plasma. All the models gave similar rank order results with respect to bioavailability differences between the three treatments.Analysis of the data by different methods suggests that pelletised doxycycline is bioequivalent to the reference product when taken in the absence of food. A standardized feeding regimen affected the rate, but not extent of absorption of doxycycline from the pelletised formulation.
Influence of food on the bioavailability of diltiazem and two of its metabolites following the administration of conventional tablets and slow‐release capsules
Authors: Souich P. Du , Lery N. , Lery L. , Varin F. , Boucher S. , Vezina M. , Pilon D. , Spenard J. , Caillé G. 
Published: October 2006

AbstractThe influence of food on the bioavailability of a conventional tablet and of a slow‐release capsule of diltiazem was investigated in two separate groups of 24 healthy volunteers in two open crossover studies. Diltiazem, as a conventional tablet (2 × 30 mg, first group) or as a slow‐release capsule (120 mg SR, second group), was administered in a fasting condition and 30 min after a breakfast of 784 kcal (23 per cent proteins, 55 per cent lipids, and 22 per cent of carbohydrates). Multiple blood samples were withdrawn during the next 24 h and diltiazem, desmethyldiltiazcm, and dcacctyldiltiazcm were assayed by HPLC. Neither the rate of absorption, assessed by the rate constant of absorption, the peak plasma concentration, and the time required to reach the peak, nor the amount of drug reaching the systemic circulation, assessed by the area under the plasma concentration time curve (AUC∞) were influenced by food, and that independently of the formulation. Compared to the fasting experiment, food did not affect either the rate of formation or the AUC∞ of desmethyldiltiazem or deacetyldiltiazem. The results of the present study show that the relative bioavailability of the single dose of diltiazem administered as a slow‐release capsule is significantly higher (69 per cent) than that estimated after the administration of diltiazem in a conventional tablet. It was concluded that food does not influence the bioavailability of diltiazem administered as a conventional tablet or as a slow‐release formulation.
Multiple‐dose propranolol administration does not influence the single dose pharmacokinetics of quinapril and its active metabolite (quinaprilat)
Authors: Horvath A. M. , Pilon D. , Caillé G. , Colburn W. A. , Ferry J. J. , Frank G. J. , Lacasse Y. , Olson S. C. 
Published: October 2006

AbstractTo evaluate the influence of multiple dose propranolol administration on the single dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, a drug‐drug interaction study was performed in ten healthy volunteers. Each subject received a single 20 mg quinapril oral dose on Days 1 and 16 of the study. Oral propranolol doses of 40 mg BID were initiated on Day 3, titrated gradually to 80 mg TID by Day 10, and continued at 80 mg TID through Day 17. Comparable mean quinapril pharmacokinetic parameter values as well as comparable mean quinaprilat pharmacokinetic parameter values determined following quinapril administered alone and following quinapril administered with propranolol, indicate that propranolol does not alter the single dose pharmacokinetics of quinapril or quinaprilat.
Absorption and disposition of a new low‐dose combination formulation of hydrochlorothiazide and triamterene
Authors: Williams R. L. , Lin E. T. , Liang‐Gee W. , Blume C. D. , Benet L. Z. 
Published: October 2006

AbstractTwo studies are reported that assess the bioequivalence of a new half‐strength drug combination containing 25 mg hydrochlorothiazide and 37·5 mg triamterene compared to a full‐strength formulation containing 50 mg hydrochlorothiazide and 75 mg triamterene. The first study (I) compared the absorption and disposition of the two drugs after administration of two tablets of the half‐strength product as a single dose compared to a single dose of the full‐strength product. The second study (II) assessed the bioavailability of the new product given as a single tablet on two occasions separated by an interval of 12 h compared to the full‐strength product given as a single dose. Urine parameters in the first study indicated bioequivalence of the half‐strength to the full product for both rate and extent of absorption. When given in divided doses, the half‐strength product demonstrated bioequivalence to the full‐strength product for extent of absorption. Additional data from the second study suggest that absorption of triamterene is greater when given in smaller divided doses and when given at night.