bluuebunny/crossref_metadata_2025 huggingface dataset:
Cimetidine inhibition of theophylline elimination: The influence of adult age and the time course
Authors: Adebayo G. I. , Coker H. A. B.
Published: October 2006

The effect of placebo or cimetidine at a dose of 1 g daily on theophylline elimination was studied in a double‐blind control manner in twelve healthy adult males aged 19–31 years. In a group of six, placebo had no effect on any of theophylline half‐life (t1/2), volume of distribution (Vd), and total body clearance (CL). In another group of six, theophylline t1/2 rose significantly from 5.48 to 9.04 h (p < 0.001) after 48 h and to 8.98 h (p < 0.001) after a week pretreatment with cimetidine. Correspondingly, CL (ml min−1kg−1) fell to 0.66 (p < 0.025) and 0.60 (p < 0.01). Changes after 48h pretreatment were not different from those after a week pretreatment. Seven days after the last cimetidine dose, theophylline disposition had reverted to the control level. There was no significant change in Vd. In five elderly subjects aged 56–68 years, a week of dosing with cimetidine caused a rise in t1/2 (7.17 h to 10.39 h; p < 0.001) and a fall in CL (0.77 ml min−1kg−1 to 0.53 ml min−1kg−1; p < 0.005) without significantly altering Vd. In two subjects, there was restoration of theophylline disposition to the control level 72 h after cessation of cimetidine intake. Changes in the elderly were not significantly different from those in the younger ones.

Data indicate that cimetidine–induced impairment of theophylline disposition is of rapid onset, has rapidly attainable maximum effect, and is rapidly reversible. Furthermore elderly individuals are just as susceptible to it as the younger adults.
Drug absorption evaluation in the presence of changes in clearance: An gorithm and computer program for deconvolution with exact clearance correction
Authors: Veng‐Pedersen Peter
Published: October 2006

Most commonly drug absorption is evaluated with a reference dosing given on separate occasions. The assumption that no change in drug disposition is taking place between the drug administrations is often violated resulting in errors in the calculations. A novel deconvolution method is presented which exactly compensates for a change in drug clearance. The method is based on a model independent disposition decomposition‐recomposition technique. The distribution function is obtained from an i.v. administration by disposition decomposition. This distribution function is assembled together with the elimination kinetics containing the perturbed clearance to construct the perturbed disposition function in the subsequent disposition recomposition operation. The perturbed absorption response is finally deconvolved using the corresponding perturbed disposition function. It is shown that the perturbed clearance can be obtained from the log‐linear terminal disposition phase once the distribution function has been obtained from an i.v. administration. The proposed method is implemented in an algorithm and computer program DCONB and demonstrated using human cimetidine drug level data from an i.v. and oral administration. The usage of DCONB is identical to DECONV previously published. It requires only regular sums of exponentials to be fitted to drug level data. Such fittings are routinely done in pharmacokinetics thereby enabling DCONB to be implemented very simply.
Pharmacokinetic and pharmacodynamic studies of felodipine in healthy subjects after various single, oral and intravenous doses
Authors: Edgar Boo , Regårdh Carl G. , Lundborg Per , Romare SÖRen , Nyberg Gunnar , Rönn Ola
Published: October 2006

The objective of this single‐dose study was to evaluate the pharmacokinetics and haemodynamic changes in healthy male subjects following the administration of three oral (5, 15, and 40 mg) and two intravenous (1 and 3 mg) doses of felodipine, a new calcium antagonist with a selective effect on the peripheral resistance vessels.

Felodipine was rapidly absorbed within 1 h when administered as an oral solution, but underwent extensive presystemic elimination. The systemic availability varied between 10 and 23 per cent. The disposition was adequately described by a two‐compartment model: the disposition was essentially dose‐independent up to 40 mg orally and 3 mg intravenously.

Felodipine produced significant dose‐dependent reduction of diastolic blood pressure and a significant reflexogenic increase in heart rate, without having any major effect on systolic blood pressure. These changes indicate that felodipine acts predominantly as an arteriodilator. The decrease in diastolic blood pressure and increase in heart rate were closely correlated with the plasma concentrations of unchanged felodipine, being maximal at 0.5 h and lasting for at least 4 h after the highest dose.
Theophylline tissue partitioning and volume of distribution in normal and dietary‐induced obese rats
Authors: Shum Linyee , Jusko William J.
Published: October 2006

Theophylline tissue distribution was examined in normal and dietary‐induced obese Sprague‐Dawley rats following constant infusion to steady‐state. Theophylline distribution was linear among all tissues and uniform throughout body water spaces. The apparent distribution coefficient, Kd,app (tissue: serum concentration) ranged from 0.55 to 0.69 for all lean tissues, but averaged 0.08 in fat. Obese rats had a consistently higher Kd,app in several tissues including muscle, heart, and liver caused by reduced (from 42 to 33 per cent) serum protein binding. Muscle slice uptake of theophylline from buffer was similar in normal and obese animals, confirming serum binding as the factor altering Kd,app. The conceptual and applied bases of calculating and measuring steady‐state volume of distribution (Vss) by various methods were explored. The physiological perturbations of theophylline Vss by obesity can be accounted for by alterations in serum binding and expanded lean and fat tissue masses, rather than changes in tissue partitioning.
Single‐dose pharmacokinetics and bioavailability of famotidine in man. Results of multicenter collaborative studies
Authors: Yeh K. C. , Chremos A. N. , Lin J. H. , Constanzer M. L. , Kanovsky S. M. , Hucker H. B. , Antonello J. , Vlasses P. , Ryan J. R. , Williams R. L.
Published: October 2006

Pharmacokinetics and bioavailability of famotidine, a new H2‐receptor antagonist, were investigated in healthy subjects in five clinical studies. Linear pharmacokinetics were observed following either intravenous or oral administration. Plasma clearance averaged 463 ml min−1. Renal clearance averaged 310 ml min−1, which exceeded the glomerular filtration rate. Renal excretion was the major route of elimination. Urinary recovery of unchanged drug following intravenous administration was about 67 per cent. Famotidine plasma half‐life was approximately 2.6h. Oral absorption was incomplete. The bioavailability averaged 43 per cent of the dose.
Pharmacokinetics of non‐prescription sympathomimetic agents
Authors: Chua S. S. , Benrimoj S. I. , Triggs E. J.
Published: October 2006

The pharmacokinetics of non‐prescription sympathomimetic agents are discussed with respect to absorption from the gastrointestinal tract, volumes of distribution, metabolism and renal excretion. Where specific data are not available, postulations are made with inference from the chemical structures of these agents, or from studies with other drugs. No studies on hypertensive patients have been found, but attempts are made to correlate any possible changes in the pharmacokinetics of these sympathomimetic agents to hypertensive patients as a high proportion of the elderly population is hypertensive. Sympathomimetic agents with lesser polar hydroxl groups, for example, are thought to be more lipophilic and are more readily absorbed from the gastrointestinal tract, have higher volumes of distribution, and are more extensively metabolized. Major metabolic pathways include oxidation, deamination, demethylation, and conjugation. Most of these agents are excreted primarily through the kidneys and due to their basic nature, the rate of excretion is dependent on urinary pHs. Any alteration in kidney functions such as in the aged is, therefore, expected to have some clinical significance on the pharmacokinetics of these agents.
Nonlinear least‐squares regression analysis by a simplex method using differential equations containing michaelis‐menten type rate constants
Authors: Murata Kazuo , Kohno Keiichi
Published: October 2006

Computer curve fittings were carried out to observed data as well as theoretically generated plasma concentrations of several drugs, using differential equations which contained nonlinear Michaelis‐Menten type rate constants to discuss problems of initial parameter estimation in pharmacokinetic analysis. Calculation based on two different algorithms, each carried out by using SIMP (simplex method) and NONLIN (modified Gauss‐Newton method) produced similar results. However, occasional divergence or unreasonable solutions occurred in a later case, when assumed values of Km and Vmax were used as initial parameters. A combined use of SIMP and NONLIN in which calculated values by SIMP were used as initial values for NONLIN, was shown to be effective to analyse plasma concentration data of indocyanine green bearing difficulty in estimating initial values. It is suggested that the successive method is useful for the curve fitting of plasma concentration with nonlinear pharmacokinetic rate processes.
Effect of bupropion on cimetidine and ranitidine absorption in rats
Authors: Tanira Musbah O. M. , Kaka Juzar S. , Al‐Khamis Khalil I.
Published: October 2006

Cimetidine and ranitidine absorption were studied in rats, alone or in combination with concurrent but separate bupropion oral admininstration. Blood samples were collected before and 0·25, 0·5, 0·75, 1·0, 1·5, 2·0, 3·0, 4·5, and 6·0h after dosing. In ranitidinetreated rats, an exta blood sample at 8h was collected. Assays of cimetidine and ranitidine were carried out using a HPLC method. Mean cimetidine plasma concentrations on concurrent bupropion administration at 0·25 and 0·5 h were approximately 2 and 1·5 times compared to the control. Similarly, mean ranitidine plasma concentrations with bupropion combination at 0·25 and 0·5 h were significantly different and approximately 2 and 3 times higher. Time of maximum concentration for cimetidine and ranitidine on combination were reduced to almost half of the control value. However, only the time of maximum concentration for cimetidine showed statistically significant difference. No significant differences were observed between AUCs, maximum concentrations, and half‐lives of cimetidine and ranitidine compared to their respective controls. The results suggest that concurrent bupropion admininstration may affect the rate but not the extent of absorption of cimetidine and ranitidine.
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

An 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

Plasma 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

The 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

The 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

An 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

Arbaprostil 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

The 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

We 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

Two 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

The 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

Eight 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

Gastrointestinal 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

This 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

A 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

The 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

To 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

Two 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.
First‐pass metabolism of acetaminophen in rats after low and high doses
Authors: Hirate Junji , Zhu Chun‐Yan , Horikoshi Isamu , Bhargava Vijay O.
Published: October 2006

The first‐pass metabolism of acetaminophen was examined in rats after the administration of 15, 30, 150, and 300 mg kg−1 doses by intra‐arterial, intravenous, portal vein, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5 h after drug administration. The first‐pass effect after oral administration (oral extraction) was extensive (Eo = 0·34–0·50) at all doses administered. Calculation of the relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction of acetaminophen indicated that the major contribution was due to the gastrointestinal tract at all doses studied (Eg = 0·33–0·50). At higher doses (150 and 300 mg kg−1) clearance was lower possibly due to the saturation of acetaminophen sulfate formation. However, even at these high doses, the contribution of the gastrointestinal mucosa to the oral extraction remained unchanged. Therefore, it appears that the apparent dose‐dependent characteristics of acetaminophen metabolism may be due to the saturation of acetaminophen sulfate formation in the liver.
Pharmacokinetics and absolute bioavailability of ibuprofen after oral administration of ibuprofen lysine in man
Authors: Martin W. , Koselowske G. , Töberich H. , Kerkmann Th. , Mangold B. , Augustin J.
Published: October 2006

The lysine salt of d, l‐2‐(4‐isobutylphenyl)‐propionic acid (ibuprofen lysine) was administered as a single oral dose of 500 mg by means of commercially available coated tablets (Imbun®). To assess the absolute bioavailability of ibuprofen after its oral application as a lysine salt, intravenous injections of ibuprofen solutions containing 200 mg and 400 mg of the drug served as reference application. In a partially randomized cross‐over design, 8 healthy male volunteers received three different single dose administrations which were separated by wash‐out periods of 4 days each. Ibuprofen plasma concentrations were determined by HPLC using direct injection, pre‐column enrichment and column switching techniques. From the results of intravenous injections one can deduce linear ibuprofen pharmacokinetics within the considered dosage range, with corresponding AUC0−∞ values of 3786 μg min ml−1 and 7260 μg min ml−1 for the 200 mg and 400 mg doses, respectively. The values of plasma clearances as well as those of different volumes of distribution showed remarkable constancy after evaluation from both intravenous injections. The absorption of orally administered ibuprofen lysine proved to be rapid, resulting in a mean peak plasma level (Cmax) of 31 μg ml− ibuprofen and in a mean time to peak (tmax) of 45 min. The absolute bioavailability of ibuprofen amounts to 102·7 percent, indicating a complete absorption of ibuprofen when administered as its lysine salt. Drug tolerability was excellent for the oral administration of ibuprofen lysine as well as for the intravenous treatments with ibuprofen free acid. Only mild and transient adverse drug reactions such as mild burning or dragging sensation during injection or mild redness at the site of injection were reported.
Effects of cefotaxime on the serum protein binding of sulfisoxazole
Authors: Souich P. Du , Calvo R. , Erill S.
Published: October 2006

The possible acylating effects of cefotaxime on sulfisoxazole binding to serum proteins were evaluated in vitro in samples of human sera incubated with 50–1000 μ ml−1 cefotaxime at 37° for 1 h and then dialyzed against saline. This incubation resulted in concentration‐related increases in the free fraction of sulfisoxazole (+25 per cent, +30 per cent, and +45 per cent, with 250, 500, and 1000 μ ml−1 cefotaxime, respectively). Sulfisoxazole binding was also studied in samples of sera from patients given prophylactic cefotaxime (3 gd−1, IV) following elective surgery. Sulfisoxazole free fraction increased from 7·6 ± 0·7 per cent in samples obtained before starting treatment to 9·2 ± 0·8 per cent 24 h thereafter, and to 10·4 ± 1·0 per cent after 5 days of treatment, but this difference was not statistically significant. A Scatchard plot of pooled samples showed a reduction in overall affinity (from 2·38 × 10−4M to 1·77 × 10−4) without changes in the number of binding sites. The effects of cefotaxime on sulfisoxazole binding and kinetics were also studied experimentally in the rabbit. Treatment with 30 mg kg−1 cefotaxime t.i.d. for 2 days increased the unbound fraction of sulfisoxazole in vivo, from 17·2 ± 2·9 per cent to 27·3 ± 3·6 per cent (p < 0·02). Treatment with high doses of cefotaxime, and perhaps other 3‐acetoxymethylcephalosporins, may result in changes in the serum protein binding of some acidic drugs.
Activation of beclomethasone dipropionate by hydrolysis to beclomethasone‐17‐monopropionate
Authors: Würthwein Gudrun , Rohdewald Peter
Published: October 2006

The relative affinity of beclomethasone (B), beclomethasone‐17‐monopropionate (17‐BMP), beclomethasone‐21‐monopropionate (21‐BMP), and beclomethasone dipropionate (BDP) has been determined. BDP binds to the glucocorticoid receptor with about half the affinity of the potent glucocorticoid dexamethasone (Dexa), B was found to be 0·75 times less active than Dexa. The 21‐BMP has no binding affinity whereas the 17‐BMP is about 13 times as potent as Dexa. The affinity data indicate that metabolism of BDP to 17‐BMP is an important activation step. To evaluate the relationship between local and systemic activity incubation studies with BDP in human lung, simulated gastric and intestinal fluid and plasma were performed. In cytosol from human lung cells BDP is hydrolysed rapidly to the more stable 17‐BMP. During gastric passage BDP is stable but is immediately hydrolysed to 17‐BMP in intestinal fluid. In human plasma BDP is hydrolyzed to 17‐BMP and an interesterification of 17‐BMP to the inactive 21‐BMP was also found.
Bioavailability and cardiovascular safety of dexatrim® (phenylpropanolamine hydrochloride) from a controlledrelease caplet
Authors: Shargel Leon , Silverman Harold I. , Cohen Peri , Brisson Jerry , Dennis Susana
Published: October 2006

The bioavailability and pharmacokinetics of phenylpropanolamine hydrochloride (PPA HCl) from a Dexatrim® controlled‐release (CR) caplet and solution was studied. Each subject (n = 12) received either a 75 mg PPA HCl CR caplet once daily or a 25 mg PPA HCl solution given three times a day. All subjects received the medication for 4 consecutive days. On Day 1, the mean ± SEM, AUC, tmax, and Cmax values were 1651 ± 127 ng x h ml−1, 4·5 ± 0·26 h and 143 ± 13·5 ng ml−1, respectively, for the CR caplet and 1716 ± 90·3ng × h ml−1, 1·25 ± 0·08 h and 126 ± 5·8 ng ml−1 for the solution, respectively. At steady state (Day 4), the mean ± SEM, AUC, tmax, and Cmax values were 1832 ± 101 ng x h ml−1, 4·17 ± 0·17 h and 151 ± 6·5 ng ml−1, respectively, for the CR caplet and 2014 ± 116 ng x h ml−1, 1·33 ± 0·09 h and 143 ± 8·7 ng ml−1, respectively, for the solution. The data from Day 1 were fitted to an oral one compartment model with a first order absorption rate constant, kA, first order elimination rate constant, k and lag time. The mean ± SEM, kA, elimination half‐life and lag time for PPA HCl from the CR caplet were 0·488 ± 0·182 ng h ml−1, 5·84 ± 1·66 h and 0·394 ± 0·224 h, respectively. The mean ± SEM, kA, elimination half‐life and lag time for PPA HCl from the solution were 2·87 ± 1·51 ng x h ml−1, 3·73 ± 1·21 h, and 0·325 ± 0·101 h. respectively. The smaller apparent kA and longer elimination half‐life for PPA HCl from the CR caplet is due to the slow release of PPA HCl, thereby slowing its absorption producing sustained plasma drug concentrations. Blood pressures (supine and sitting) and heart rates measured at the time of blood sampling after the administration of the PPA HCl dosage forms demonstrated no clinically significant relationship between cardiovascular response and PPA HCl plasma concentration. These data demonstrate the bioavailability and pharmacokinetics of PPA HCl from a CR caplet and an immediate release solution.
Pharmacokinetics of pafenolol in the rat: A suitable model for studying absorption mechanisms of a drug exhibiting unusual absorption properties in man
Authors: Lenneras Hans , Regårdh Carl G.
Published: October 2006

The pharmacokinetics of pafenolol, a highly selective β1‐adrenoceptor antagonist, have been studied in starved and unstarved rats. Separate groups received intravenous doses (0·3 and 3·0 μmol kg−1) and oral doses (1 and 25 μmol kg−1). The systemic clearance of pafenolol was constant in the dose range investigated where the absolute oral bioavailability increased from 15 to 27 per cent in the starved and from 9·1 to 21 per cent in the unstarved rats, when the oral dose was raised from 1 to 25 μmol kg−1. The blood concentration profile after an oral solution of pafenolol exhibited two peaks in the majority of the rats. The major part of the absorption was associated with the second peak which appeared about 4 h after dosing in both starved and unstarved rats. Food lowered the degree of bioavailability and shifted the t, to about 1 hour compared to half an hour in starved rats. The low bioavailability was primarily due to incomplete uptake from the gastrointestinal tract. Our study shows that pafenolol is absorbed in a similar way to that in man. The mechanisms behind the dose‐dependent bioavailability and the two peaks in the absorption profile after an oral solution will be further explained in the rat.
Regional pharmacokinetics II. Experimental methods
Authors: Upton Richard N. , Runciman William B. , Mather Laurence E.
Published: October 2006

Regional pharmacokinetics is the study of the drug concentrations in specific regions of the body. It allows greater insight into the mechanisms of drug disposition than the study of systemic blood concentrations. Experimental methods in regional pharmacokinetics and their applications and limitations are reviewed. Post‐mortem tissue biopsies give the drug concentrations in highly specific regions of the body, but require a large number of animals. Serial tissue biopsies yield the time‐course of drug concentrations in individual animals, but have limited applications. Regional blood sampling in vivo requires catheterization of blood vessels and a measure of regional blood flow, but allows repeated measurements of the time‐course of regional drug concentrations in an individual. In contrast, artificially perfused regions allow greater control of perfusate flow and composition, but are less representative of the in vivo situation. These factors can be retained in some animals by surgically transplanting organs to another location to increase access. Tissues slices and cell cultures can examine drug uptake in the absence of perfusion, and tissue homogenates can be used to study the in vitro rates of drug metabolism and tissue drug binding.
Central nervous system uptake kinetics of pentylenetetrazol in the developing rat
Authors: Haberer Lynda J. , Pollack Gary M.
Published: October 2006

The present investigation was undertaken to examine the brain uptake kinetics of the central nervous system (CNS) stimulant pentylenetetrazol (PTZ) during postnatal development. This study represents part of an ongoing effort to develop an appropriate seizure model for investigations of anticonvulsant action in the developing rat. The systemic pharmacokinetics of PTZ were examined in male and female adult animals following both intravenous (IV) and subcutaneous (SC) injection. PTZ administered SC was absorbed rapidly and was completely bioavailable in both genders. No statistically significant gender‐dependent differences in the disposition of PTZ were identified. To examine the CNS uptake kinetics of PTZ, animals of four different age groups (5, 10, 20, and 60 days postnatal) received timed SC infusions of PTZ. Significant age‐related differences in the rate of uptake of PTZ into the CNS were observed. These differences paralleled the previously reported age‐dependent changes in the dose of PTZ required to elicit seizure activity. The results of this investigation indicate that the apparent age‐related change in sensitivity to the convulsant effects of PTZ is due in part to age‐dependent uptake of the convulsant into brain tissue.
Age‐dependent changes in first‐pass metabolism of acetaminophen in rats
Authors: Hirate Junji , Zhu Chunyan , Horikoshi Isamu , Bhargava Vijay O.
Published: October 2006

The contribution of gastrointestinal tract (GIT), liver, and lung towards the first‐pass metabolism of acetaminophen was examined using 3‐week‐old, 10‐week‐old and 1‐year‐old rats after administration of 30mgkg−1 doses by intra‐arterial, intravenous, intraperitoneal, and oral routes. Plasma concentrations of acetaminophen and its two major metabolities, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5h after drug administration. Total oral extraction of acetaminophen was extensive in 10‐week‐old and 1‐year‐old rats (Eo = 0·46) and the major contribution to the overall first‐pass metabolism was due to the GIT (Eg = 0·50–0·53). Oral extraction in 3‐week‐old rats was minimal (Eo = 0·10) and there did not appear to be an extraction by the GIT (Eg = 0·00). These results suggest that the ability of GIT to metabolize acetaminophen to glucuronide and sulfate is undeveloped in the infant rats. No changes in the contribution of different organs to the first‐pass metabolism of acetaminophen was observed 10 weeks after birth. Pharmacokinetic parameters for acetaminophen in infant rats (3‐week‐old) and 10‐week‐old rats were similar after drug administration by the intra‐arterial and intravenous routes.