bluuebunny/crossref_metadata_2025 huggingface dataset:
The pharmacokinetics of exaprolol and propranolol in rats with interrupted enterohepatic circulation
Authors: Motheová O. , Bezek Š. , Ďurišová M. , Faberová V. , Zemánek M. , Mišánikova K. , Trnovec T.
Published: October 2006

The pharmacokinetics of two beta adrenoceptor blocking drugs, exaprolol and propranolol, in rats with interrupted enterohepatic circulation was studied. The tritium‐labelled drugs were given intravenously to four groups of rats: control, bile‐duct cannulated, bile‐duct ligated, and pretreated with neomycin. Plasma levels and excretion were observed up to 96 h after administration. The pharmacokinetic parameters show an enhanced plasma elimination of both drugs at interrupted enterohepatic circulation compared to the control group. Significant changes were observed in the excretion pattern with bile‐duct cannulated and bile‐duct ligated rats, while the total radioactivity excreted in urine and faeces does not differ between control and neomycin pretreated rats.
Intra‐ and intersubject variation of erythromycin absorption from single‐unit and multiple‐unit enteric‐coated products
Authors: Graffner C. , Josefsson K. , Stockman O.
Published: October 2006

Based on the in vitro dissolution test for erythromycin capsules introduced in USP XX. Suppl. 3, there are no reasons to expect any difference in bioavailability after administration of two enteric‐coated products, tablets and pellets in hard capsules.

The present results in vivo are contradictory and, following duplicate administrations of the two preparations to 12 volunteers after a standardized breakfast, it is apparent that the multiple‐unit, pellets, produce a better reproducibility in absorption both within and between subjects than the single‐unit tablets. All subjects attained measurable levels of erythromycin on all occasions after administration of pellets, while levels were below the detectable limit on six out of the 24 occasions tested after administration of tablets. The better reproducibility of serum levels after pellets than after tablets was also shown in a descriptive way and is given as a low median discrepancy value of 23.5 per cent (moderate) compared to 73.2 per cent (large).
Brain uptake of labelled adiphenine in rats
Authors: Michelot J. , Moreau M. F. , Veyre A. , Labarre P. , Meyniel G.
Published: October 2006

This study describes the behaviour of a dual labelled drug, adiphenine, in the rat brain. Macroautoradiographies show images of the brain at different times after injection. Some of the tissue metabolites are identified at the brain level and the passage of the blood brain barrier is compared with tritiated water.

The obtained data give very interesting indications on the blood brain distribution and on the metabolism at the brain level. Different techniques of high pressure liquid chromatography, macro‐ and histoautoradiographies allowed us to visualize how the drug is fixed on cerebral structures, giving indications on its mechanism of action.

This fat soluble compound freely crosses the normal blood brain barrier and if labelled with the appropriate emittor could be very useful in nuclear medicine to obtain imaging of the brain.
Bioavailability in man of atenolol and chlorthalidone from a combination formulation
Authors: McAinsh James , Holmes Brian H. , Fitzsimons Timothy J. , Young Jean
Published: October 2006

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles and urinary recoveries of both atenolol and chlorthalidone were studied following the administration of the drugs as a fixed combination (‘Tenoret 50’), as a free combination, and individually, at doses of 50 mg atenolol and 12.5 mg chlorthalidone.

There were no statistically or clinically significant differences between the three treatments of atenolol in terms of individual blood levels, areas under the curve, and urinary excretion. The mean half‐lives were between 5 and 7h, in agreement with other published data. The variation in peak systemic levels is less than that observed for a number of other β‐blocking drugs and is of the same order as seen in other investigations involving atenolol. Thus the bioavailability of atenolol from the fixed combination is equivalent to that from the free combination and from the atenolol tablet.

The mean peak blood concentrations of chlorthalidone were 0.94, 1.00, and 0.99 μg ml−1 for the fixed and free combinations and the chlorthalidone tablet, respectively. The mean areas under the curve were also similar as were the mean half‐lives and urinary recovery. There were no statistically or clinically significant differences between the three treatments. Thus the bioavailability of chlorthalidone from the fixed combination is equivalent to that from the free combination and from the chlorthalidone tablet.

It is concluded that combining chlorthalidone and atenolol in a single tablet does not affect the systemic bioavailability of either component.
Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5‐hydroxy‐ and N4‐acetylmetabolites in man
Authors: Vree T. B. , Vree T. B. , Hekster Y. A. , Tijhuis M. W. , Termond E. F. S. , Nouws J. F. M.
Published: October 2006

Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half‐lives of sulfatroxazole and its metabolites 5‐hydroxysulfatroxazole and N4‐acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N4‐acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half‐life of N4‐acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation‐deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5‐hydroxy‐ and N4‐acetylsulfatroxazole. Inhibition of the N4‐acetylmetabolite favours the deacetylation, which results in an increase of the T1/2 of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4‐acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes.
Inhibition of tumor cell growth in vitro and in vivo by 2‐methyl 9‐hydroxyellipticinium entrapped within phospholipid vesicles
Authors: Sautereau A. M. , Cros S. , Tocanne J. F.
Published: October 2006

Encapsulation in liposomes of the antitumoral drug 2‐methyl 9‐hydroxyellipticinium and the consequences of its cytoxicity in vitro on L1210 leukemia cells and on its antitumoral activity in vivo on leukemic mice inoculated with L1210 cells are described. Provided the drugs is dissolved in the buffer below its critical micelle concentration (10−4M), it can be encapsulated in lipid vesicles with a very good yield in the form of a very stable combination with the lipids. The in vitro experiments show that 2‐CH3 9‐OH‐ellipticinium is less cytotoxic against L1210 cells when entrapped than when free in solution. The in vivo experiments on tumor‐bearing mice show that encapsulation of the drug reduces its toxicity. Encapsulation maintains the antitumoral activity of the drug or increases it if the leukemia is delayed (104 cells injected per mouse instead of 105 cells per mouse).
Modeling the pharmacokinetics and pharmacodynamics of trimazosin
Authors: Kelman A. W. , Meredith P. A. , Elliott H. L. , Reid J. L.
Published: October 2006

The pharmacokinetics and pharmacodynamics of trimazosin are described following both intravenous and oral administration to 6 normotensive, male volunteers. The IV and oral drug and metabolite (1‐hydroxytrimazosin) concentration data are fitted simultaneously to the same pharmacokinetic model. The pharmacodynamic response, change in systolic blood pressure following 5 min in the erect posture, is described using several possible models. The most efficient is one which attributes the response to both the parent drug and its principal metabolite. The response following oral administration is also consistent with this model.

It appears that the reduction in blood pressure following administration of trimazosin at steady state may be governed by the concentration of metabolite.
The effect of activated charcoal on mouse sleep times induced by intravenously administered hypnotics
Authors: Adler Lauri J. , Waters Donald H. , Gwilt Peter R.
Published: October 2006

The effect of orally administered activated charcoal (AC) on the sleep times of mice following intravenous injection of various hypnotics was investigated. Preliminary studies with phenobarbital (Pb) showed that a linear relationship exists between the Pb‐induced sleep time and the logarithm of the Pb dose in both control and AC treated mice. Half‐lives of Pb in the two groups were estimated to be 8·1 and 0·9h. respectively. A linear decline in Pb‐induced sleep time with increasing dose of AC was observed up to a maximum effective dose of AC beyond which dose increments caused no further reduction in sleep time. A similar relationship was observed between sleep time and the concentration of sodium sulfate in which the AC was suspended.

AC treatment resulted in an 82–88 per cent reduction in sleep time induced by administration of phenobarbital, methyprylon. glutethimide, ethchlorvynol, and methaqualone, AC had no significant effect on sleep time following amobarbital or pentobarbital administration.
The influence of sucralfate on ibuprofen absorption in healthy adult males
Authors: Anaya Arturo Lopez , Mayersohn Michael , Conrad Kenneth A. , Dimmitt Dan C.
Published: October 2006

Sucralfate (Carafate®) is a new anti‐ulcer agent the effects of which are mediated locally in the gastrointestinal tract. The use of this compound in conjunction with ulcerogenic drugs such as ibuprofen may represent a means of reducing gastrointestinal irritation. Combined oral therapy, however, requires evaluation of a potential interaction in absorption between those agents. The purpose of this study was to examine the influence of sucralfate coingestion on ibuprofen absorption. Twelve normal, healthy male subjects ingested a single oral 400 mg dose of ibuprofen alone or with sucralfate given as 1 g doses four times a day for 2 days prior to and during the study. Ibuprofen serum concentrations were measured for 12 hours following dosing. Parameters associated with rate of absorption (i.e. Cmax, tmax, Ka) were significantly altered in the presence of sucralfate (p < 0.05). In contrast, the relative bioavailability of ibuprofen was not significantly different between treatments (p > 0.05). Therefore, sucralfate does not alter the extent of ibuprofen absorption and would not be expected to change the response to that anti‐inflammatory agent.
The relationship between drug input and mean residence time in the body
Authors: Bialer Meir , Look Zee M. , Silber B. Michael , Yacobi Avraham
Published: October 2006

The relationship between the mean residence time after oral dosing or any other non‐instantaneous mode of administration (MRTni) was explored by a series of computer simultations. MRTni was calculated from the ratio of AUMC to AUC (where AUC and AUMC are the zeroth and first statistical moments, respectively, of the drug concentration‐time curve). A continuous linear relationship between MRTni and 1/ka or 1/kO was observed. In the ‘flip‐flop’ case where ka < K (where K is the elimination rate constant), the extrapolation from t* to infinity (where t* is the last observed plasma concentration) should be done using ka instead of K. If K is used, underestimated values of MRTni will be obtained. The findings from this investigation have practical application in the design and pharmacokinetic evaluation of novel sustained‐release dosage forms.
The effect of administration of phenytoin on the pharmacokinetics of isoxicam
Authors: Caillé G. , du Souich P. , Larivière L. , Vézina M. , Lacasse Y.
Published: October 2006

This study was designed to determine whether the disposition of isoxicam is influenced by the coadministration of another acidic drug, highly bound to plasma proteins and extensively metabolized, i.e., phenytoin. Ten healthy volunteers received an oral dose of 200 mg of isoxicam prior to and following the oral administration of phenytoin (100 mg) twice a day for 10 days. Eleven blood samples were drawn during the period following each dose of isoxicam. The area under the isoxicam plasma concentration‐time curve (AUC∞) increased from 389 ± 66 to 464 ± 62 μg h ml−1 (± SEM) (p < 0.05) after treatment with phenytoin. This increase was due to an increase in isoxicam bioavailability; the absorption rate constant for isoxicam increased correspondingly from 0.34 ± 0.06 to 1.16 ± 0.38 h−1 (p < 0.05). Distribution and clearance of isoxicam were probably not affected as its half‐life was not changed, its plasma peak concentration increased, and the time to reach this peak decreased. It is concluded that phenytoin increases the rate and extent of absorption of isoxicam.
Single intravenous dose and steady‐state oral dose pharmacokinetics of nicardipine in healthy subjects
Authors: Wagner John G. , Ling Teck L. , Mroszczak Edward J. , Freedman Donna , Wu Ann , Huang Bee , Massey Ian J. , Roe Robert R.
Published: October 2006

Nicardipine HCl oral doses (10–40 mg) were administered sequentially to six healthy subjects. For each regimen the capsule dose was administered every 8 hours (q 8 h) for 3 days and the plasma profiles of nicardipine and its pyridine analogue (M5) were determined following the last dose on day 4. Steady‐state plasma concentrations of nicardipine for each subject were fitted very well by the Michaelis–Menten equation. An intravenous tracer dose (0.885 mg nicardipine HCl) was administered simultaneously with the final oral dose on the fourth day of the 30 mg q 8 h regimen. The steady‐state bioavailability of nicardipine was shown to be dose‐dependent and averaged 19 per cent (10 mg), 22 per cent (20 mg), 28 per cent (30 mg), and 38 per cent (40 mg). Nicardipine undergoes linear first‐pass metabolism to M5. Other metabolic pathways are responsible for the saturable first‐pass metabolism observed for nicardipine.
Comparative quinidine plasma profiles at steady state of two controlled‐release products and quinidine sulfate in solution
Authors: Wright George J. , Melikian Armen P. , Pitts Jefferson E. , Crowe James T. , Morley Emily M.
Published: October 2006

A study was conducted to compare, at steady state, the plasma quinidine level profiles of two commercial controlled‐release products (quinidine sulfate controlled release and quinidine gluconate controlled release) with quinidine sulfate given in solution. Twenty‐four healthy volunteers entered the study and 23 completed it. Quinidine formulations were given at 600mg day−1 for 4 days in each of three periods in a randomized crossover study. In addition to frequent blood sampling on the fourth day of each period, samples were taken during the approach to steady state to confirm by minimum plasma concentrations (Cmin) that steady state had been attained. Quinidine concentrations were measured by using a high‐performance liquid chromatographic assay specific for quinidine. The bioavailability of the two controlled‐release products relative to quinidine sulfate in solution was adequate when dose correction to account for differences in quinidine base content was done. Without dose correction, the area under the plasma concentration–time curve (AUC) for the quinidine gluconate form was 85 per cent that of the solution: an amount equivalent to the relative actual amount of quinidine base in the quinidine gluconate dosage form. The maximum plasma concentration (Cmax), Cmin, peak‐to‐trough differences, and AUC from the quinidine sulfate extended‐release form given 300mg q12h were similar to the solution given 150mg q6h. With dose correction, the quinidine gluconate controlled‐release form given q12h had equivalent AUC but larger peak‐to‐trough differences than either the quinidine sulfate extended‐release product given q12h or quinidine sulfate in solution given q6h.
Pharmacokinetics of dexamethasone and its phosphate ester
Authors: Rohdewald Peter , Möllmann Helmut , Barth Jürgen , Rehder Jörg , Derendorf Hartmut
Published: October 2006

Dexamethasone in form of its phosphate was given intravenously in two different doses (1.5mg kg−1 and 15 mg). Plasma levels of the ester and dexamethasone were measured and pharmacokinetic parameters were calculated. The results indicate no dose‐dependency of the pharmacokinetic parameters in the investigated range for dexamethasone. Conversion from the prodrug to the active form was rapid; maximum dexamethasone plasma concentrations were reached after 10 min. The results were verified by dexamethasone level monitoring in patients after chronic dosing. Predicted and achieved steady state levels agreed well.
The nonlinear pharmacokinetics of prednisone and prednisolone. II. Plasma protein binding of prednisone and prednisolone in rabbit and human plasma
Authors: Ferry Jame S. J. , Wagner John G.
Published: October 2006

The protein binding characteristics of prednisone and prednisolone were determined in human and rabbit plasma and in a 4.7 per cent human serum albumin (HSA) solution. The influence of prednisolone on prednisone binding in human plasma was also examined. Prednisolone exhibited nonlinear binding and prednisone linear binding characteristics in both human and rabbit plasma. Prednisone binding was not influenced by the presence of prednisolone. Prednisone binding to HSA was linear but to a degree substantially lower than observed in human plasma, suggesting the possibility that prednisone binds to other proteins in human plasma. The results support the hypothesis that the protein binding characteristics of prednisone and prednisolone do not explain the reported nonlinear pharmacokinetics of prednisone.
Pharmacokinetics of flurbiprofen in man. I. Area/dose relationships
Authors: Szpunar G. J. , Albert K. S. , Bole G. G. , Dreyfus J. N. , Lockwood G. F. , Wagner J. G.
Published: October 2006

Flurbiprofen pharmacokinetics were studied in 15 normal male subjects after four oral doses. Plasma levels of total (bound + free) drug were monitored for 48 h and urine was collected for 96 h after the doses. All subjects demonstrated linear relationships between administered dose and total flurbiprofen AUC, indicating that oral clearance is independent of dose for the dose range evaluated in this study. Urinary recovery data indicated that the efficacy of absorption was dose independent.
High‐performance liquid chromatographic analysis, plasma protein binding and red blood cell partitioning of phenprobamate
Authors: Sun Jim X. S. , Embil Koral , Chow Diana S. L. , Lee Charles C. S.
Published: October 2006

A new high‐performance liquid chromatographic procedure for the analysis of phenprobamate, a skeletal muscle relaxant in biologic fluids was developed. The method used a C18 reverse phase column, a mobile phase of methanol/acetonitrile/ water (33:15:52), and UV detection at 215nm. The assay procedure was applied to the determination of phenprobamate binding to rat and human plasma proteins using the equilibrium dialysis method. In addition, the red blood cell/plasma partitioning was determined in the whole blood of rats and humans. Phenprobamate exhibited a moderate binding to plasma proteins of rat (74.3 ± 2.2 per cent) and human (80.5 ± 1.1 per cent). The protein binding was concentration‐independent in the range of 10 to 80μgml−1. Phenprobamate binding to plasma proteins was also determined in the presence of 10μml−1 acetaminophen. The protein binding of phenprobamate was not significantly altered by acetaminophen (74.4 ± 0.6 per cent for rat plasma; 75.7 ± 1.6 per cent for human plasma). The distribution ratios of phenprobamate between the red blood cells and plasma were greater than unity, 1.86 and 1.59 in rat and human, respectively, indicating a preferential partitioning of the drug in the red blood cells.
Pharmacokinetic analysis of sustained‐release dosage forms of theophylline in humans: Comparison of single and multiple dose studies
Authors: Hussein Ziad , Bialer Meir , Friedman Michael , Raz Itamar
Published: October 2006

A pharmacokinetic analysis of two sustained‐release dosage forms of theophylline (Theo‐Dur® and Theotrim®) was carried out following single and multiple dose administrations of the two formulations in five healthy subjects. Despite the prolonged absorption after administration of the two sustained‐release formulations, theoretical predictions of theophylline steady‐state levels following multiple dosages based upon data obtained from the single dose study, correlated with the data of the multiple dose study. This study shows that the recommended dose and dosage regimen of new sustained‐release formulations of theophylline can be based upon single dose studies. In the population studied, repetitive doses of 450mg b.i.d. of Theo‐Dur® and Theotrim® maintain steady‐state concentrations of theophylline within the drug's therapeutic window.
Amiodarone pharmacokinetics. II. Disposition kinetics following subchronic administration in rat
Authors: Weir Scott J. , Ueda Clarence T.
Published: October 2006

A 30 mg kg−1 intravenous bolus of 14C‐amiodarone (19μCi kg−1) was given to male Sprague‐Dawley rats pretreated with 0 (vehicle), 25 or 100mg kg−1 day−1 of amiodarone HCl orally for 37‐42 days to determine the effects of dose and duration of administration on the disposition kinetics of amiodarone. Serial blood samples and total urine were collected over 48 hours and assayed for 14C‐amiodarone by liquid scintillation counting following separation by HPLC. In all three groups, the blood 14C‐amiodarone concentration‐time curves declined bioexponentially with terminal half‐lives (t1/2β) ranging from 14‐22 hours. No differences in β, t1/2β, or central compartment volume (Vc) were observed between the three groups of rats. In the rats pretreated with 100 mg kg−1 day−1 of amiodarone HCl for 5‐6 weeks, amiodarone clearance (CL) and steady state volume of distribution (Vss) were reduceed 52 per cent (12.2 to 5.9ml min−1 kg−1) and 41 per cent (11.73 to 6.97 lkg−1), respectively. At the lower amiodarone daily dose, no changes in CL or Vss were observed. Negligible levels of radioactivity were detected in the urine. Amiodarone accounted for approximately 30–40 per cent of the total radioactivity in each blood specimen. This study demonstrated that CL and Vss were dose‐dependent, and that β, t½β and Vc were dose‐independent. The results further suggested that the disposition kinetics of amiodarone were independent of the duration of drug administration.
Comparative steady state bioavailability of conventional and controlled‐release formulations of albuterol
Authors: Powell Mark L. , Weisberger Miryam , Dowdy Yvonne , Gural Richard , Symchowicz Samson , Patrick James E.
Published: October 2006

A new controlled‐release (CR) dosage formulation of albuterol has been developed which is suitable for twice‐a‐day dosing. The present study was conducted in twelve healthy adult male volunteers to compare the steady state plasma levels obtained following repeated administration of a 4mg CR tablet (q12h) compared to a 2mg conventional table (q6h) for 5 consecutive days. The mean steady state plasma level‐time curves for both the CR and conventional tablet treatments were comparable over time and reproducible. There were no significant differences in the AUC or Cmax values between the two treatments. The mean 48‐h AUC values were 240.7 and 231.3h × ng ml−1 for the conventional and CR tablets, respectively, while the corresponding Cmax values ranged from 5.3 to 6.8 ng ml−1 and 5.4 to 6.5 ng ml−1. There were no significant differences in Cmin values except for one 12‐h (day 4) value. Cmin values ranged from 3.8 to 4.3 ng ml−1 and 3.0 to 4.8 ng ml−1 for the conventional and CR tablets, respectively. The data show that the 4mg albuterol CR tablet (q12h) is bioequivalent to a 2 mg conventional albuterol tablet (q6h). The CR tablet formulation will offer the advantage of increased patient compliance; additionally, the CR formulation may prove to be especially beneficial in the treatment of nocturnal asthma.
Prediction of steady‐state bioequivalence relationships using single dose data I‐linear kinetics
Authors: Jackson André J.
Published: October 2006

Simulated data using a linear one‐ and two‐compartment body model with different absorption characteristics were used to evaluate the ability of single dose bioavailability data to predict the relationships that exist at steady state. This was done by comparing the confidence intervals obtained from single and multiple dose data sets for the parameters of Tmax, Cmax, and area under the curve from time zero to infinity (AUC0‐∞). As a consequence of Tmax and Cmax decreasing and increasing from single to multiple dosing regimens, the confidence intervals for these parameters reflected these changes. The 90 per cent confidence interval expressed as a percentage of the reference mean increased or decreased for Tmax dependent upon the ratio of Ka test/Ka reference, and decreased for Cmax while the interval for AUC0‐∞ exhibited no predictable pattern and appeared to be influenced by the amount of error in the data set. Alteration of either the dosing interval or the fraction absorbed did not affect the pattern of change in the confidence intervals for Tmax and Cmax, but the latter did result in a decrease in the interval for AUC0‐∞. Analysis of the confidence intervals for Tmax, Cmax and AUC0‐∞ in bioequivalency studies for quinidine gluconate and procainamide hydrochloride following administration of single and multiple doses to different subjects appeared to be consistent with the patterns observed for the simulated data sets.
Bioavailability of propranolol hydrochloride tablet formulations: Application of multiple dose crossover studies
Authors: Eldon Michael A. , Kinkel Arlyn W. , Daniel Jane E. , Latts Jeffrey R.
Published: October 2006

Two multiple dose crossover pharmacokinetic studies were carried out to determine the steady‐state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal® tablets. In Study I, 24 healthy volunteers were dosed with 4 × 10mg test tablets, 1 × 40 mg test tablet, 4 × 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 × 80 mg test tablet, 1 × 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration‐time data for test tablets and reference tablets were superimposable in both studies.

Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady‐state. Mean AUC, Cmax, tmax, and Cmin values were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal® tablets. Therefore, the test tablets and Inderal® tablets were determined to be bioequivalent.
Effects of equimolar doses of cimetidine and ranitidine on theophylline elimination
Authors: Adebayo G. I.
Published: October 2006

The disposition of theophylline was studied on four occasions in eight healthy adult males. The control mean theophylline half‐life and clearance were 7·32 h and 0·86 ml min−1kg−1, respectively. After 5 days pretreatment with placebo the corresponding values of 7·01 and 0·88 were not significantly different, as were those of 7·43 and 0·85 after 5 days pretreatment with ranitidine (1·2g daily). Five days pretreatment with cimetidine (1·0g daily) resulted in a significant 44·4 per cent rise in the mean theophylline half‐life and a 36·1 per cent fall in clearance. The fall in clearance correlated positively (r=0·9407) with the initial value. The volume of distribution did not change significantly throughout the study period. The fact that, at as large a dose as 1·2g daily, ranitidine did not impair theophylline metabolism suggests that similar results reported earlier with therapeutic doses of 300 mg daily cannot be ascribed to the lower dose of ranitidine employed. It is also suggested that the risk of theophylline toxicity consequent on cimetidine coadministration will be more likely in individuals with initial high theophylline clearance.
Pharmacokinetics of theophylline before and after nephrectomy in dogs
Authors: Brashear Richard E. , Veng‐Pedersen Peter , Karol Michael D.
Published: October 2006

The role of the kidneys in the elimination of theophylline was directly assessed using nephrectomized dogs. Data was analyzed by two different pharmacokinetic approaches. Analysis indicated that a given dosage regimen produced significantly different serum concentrations before and after nephrectomy. Model independent pharmacokinetic analysis failed to show a significant difference in parameters. A model dependent approach, using a nonlinear regression analysis employing a linear two‐compartment model, demonstrated that the differences observed could be accounted for by a change in the first order elimination kinetics.
Multiple‐dose pharmacokinetics of the new H1‐receptor antagonist tazifylline in healthy volunteers
Authors: Bruno R. , Jullien I. , Auger J. , Iliadis A. , Dow R. , McEwen J. , Cano J. P. , Pinhas H.
Published: October 2006

The multiple‐dose pharmacokinetics of the new H1‐receptor antagonist, tazifylline, were investigated in healthy volunteers. From single‐dose data, tazifylline appeared to be rapidly absorbed (median tmax of 0·6 h) and eliminated (t1/2 □ 1·0±0·2 h). However, plasma levels measured on days 3 and 8 of the multiple‐dose regimen (10 mg b.i.d. for 8 days) indicated moderate accumulation. A two‐compartment model best described multiple‐dose data with a terminal half‐life of 15·6 ± 7·6 h consistent with twice‐daily dosing of tazifylline.
Removal of sulfonamides by hemofiltration
Authors: Yu Shue‐Sheng , Waters Donald H. , Shen Shueh‐Hui , Lempert Kenneth D. , Gwilt Peter R.
Published: October 2006

Hemofiltration is a relatively new technique for removing toxic substances from the body. Unlike hemodialysis or hemoperfusion, the driving force behind hemofiltration is ultrafiltration. There have been several studies examining the clearance of drugs by hemofiltration but to date no study has investigated in a systematic way the effects of protein binding, perfusate flow, transmembrane pressure, and the duration of treatment on drug clearance by hemofiltration. The influence of these factors on the hemofiltration clearance of three sulfonamides with differing degrees of protein binding was investigated. It was found that hemofiltration drug clearance decreased with the duration of hemofiltration and protein binding but increased with perfusate flow and transmembrane pressure.
Sustained release properties of the once daily theophylline capsule BY912 as compared with Theo–24® capsules
Authors: Jonkman J. H. G. , Steinijans V. W. , Beier W. , Van Der Boon W. J. V. , Crasmeijer G.
Published: October 2006

In a multiple dose cross‐over experiment in 12 healthy male adults the bioavailability and sustained release characteristics of new once daily BY912 400 mg theophylline capsules (= B, Byk Gulden Research Laboratories, FRG) were studied using Theo‐24® capsules (= T, Searle & Co., USA) as reference.

Both products were given once daily for a period of 7 days as an 800 mg theophylline dose at 8 am, half an hour after a standardized breakfast.

Theophylline concentrations in plasma were measured on days 1, 6, and 7 using highperformance liquid chromatography.

Significantly better sustained release characteristics, resulting in longer plateau time (t75%, 11·6 vs 9·2 h on day 6 and 13·1 vs 8·8 h on day 7) and smaller per cent peak‐trough fluctuation in the steady state (per cent PTF, 80 vs 103 per cent on day 6 and 66 vs 100 per cent on day 7), were found for B in comparison with T.

The extent of absorption on both days, however, was smaller for B compared with T (relative bioavailability 84 per cent and 81 per cent, respectively).

In conclusion, the absorption of theophylline from B resulted in a more extended shape of the plateau phase, indicating better sustained release characteristics. The extent of absorption, however, over the dosing intervals was more complete with T.
Relative bioavailability of almitrine bismesylate in humans
Authors: Stavchansky S. , Doluisio J. T. , MacLeod C. M. , Sebree T. B. , Heilman R. , Bachand R. T. , Szalkowski M. B. , Geary R. S.
Published: October 2006

Bioavailability and bioequivalency studies of almitrine bismesylate from U.S. manufactured film coated, waxed, 50 mg tablets were compared in 34 normal healthy volunteers to 50 mg European film coated, waxed and unwaxed, tablets and a 0·5 per cent (w/v) oral reference solution of almitrine bismesylate in d,1 malic acid. The U.S. manufactured formulations were 85·88 and 87·85 per cent of the calculated mean area under the individual concentration‐time curve for almitrine bismesylate reference solution compared to 88·40 and 88·86 per cent for the waxed and unwaxed film coated European tablets, respectively. The mean peak plasma concentrations for the U.S. formulations were 176·3 ng ml−1 and 180·1 ng ml−1 compared to 196·3 and 200·1 ng ml−1 for the waxed and unwaxed European formulations, respectively. Mean time to peak plasma concentrations for the two U.S. formulations and the waxed and unwaxed European formulations were 3·22, 3·33, 3·06, and 3·26h, respectively. In addition, the oral reference solution yielded a mean peak plasma concentration of 222·8 ng ml−1 and a mean time to peak plasma concentration of 2·68 h. Analysis of variance and multiple range comparisons (p < 0·05) indicated that the tablet formulations were bioequivalent. The results of this study show that the U.S. formulated almitrine bismesylate tablets exceed 85 per cent relative bioavailability with respect to the oral reference solution and are bioequivalent compared to the marketed standard European tablet formulations.
One year administration of almitrine bismesylate (vectarion) to chronic obstructive pulmonary disease patients: Pharmacokinetic analysis
Authors: Stavchansky S. , Doluisio J. T. , MacLeod C. M. , Szalkowski M. B. , Bachand R. T. , Heilman R. , Sebree T. B. , Geary R. S.
Published: October 2006

A double blind study utilizing orally administered almitrine bismesylate was conducted involving 36 stable chronic obstructive pulmonary disease (COPD) patients with hypoxia and with and without hypercapnia. The patients received 50mg tablets twice daily for 360 days. Blood samples were taken both at predose and 3 hours postdose at different periods throughout 1 year dosage regimen and plasma levels were analyzed by a GLC method using a nitrogen‐phosphorous detector. Plasma almitrine concentrations indicate large variability at each time sample. Results suggest an increasing trend in the almitrine plasma levels as a function of time. Plasma almitrine levels increased significantly (p < 0·01) between test day 14 and test day 360 (243 ± 213 per cent and 199 ± 170 per cent for predose and 3 h postdose samples, respectively) indicating that steady state is not achieved by day 14. Almitrine plasma levels appear to stabilize between test day 90 and test day 180. The effective multiple dose half‐life for almitrine bismesylate in plasma is estimated to be 32 days. About half of the patients exhibited steady state peak plasma almitrine levels above 500ng ml−1. In addition, 19 per cent of the patients achieved maximum apparent steady state almitrine levels greater than 700ng ml−1. Mean accumulation was estimated to be 4·21 ± 1·98 at one year.
The logical structure and validity of experimental designs in pharmacokinetics and clinical pharmacology
Authors: Mason Emanuel J. , Bialer Meir
Published: October 2006

Much of the literature on research design in clinical pharmacology and pharmacokinetics emphasizes statistical concerns, thus suggesting that a primary ingredient of a valid research design is an appropriate plan for statistical analysis of data. However, statistical validity is only one of several ways to evaluate an experimental study. The present paper reviews the underlying logic and sources of invalidity of experimental drug research suggesting influences and factors which may deceive or lure an experimenter into erroneous conclusions.
Pharmacokinetics of the angiotensin converting enzyme inhibitor benazepril·HCl (CGS 14 824 A) in healthy volunteers after single and repeated administration
Authors: Kaiser Günther , Ackermann Roland , Brechbühler Sylvia , Dieterle Walter
Published: October 2006

The pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril·Ȟl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once‐daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril·Ȟl was rapidly absorbed (tmax □ 0·5 h) and rapidly eliminated from plasma (t1/2 □ 0·6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax □ 1·5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t1/2 □ 2·7 h), whereas the terminal phase (t1/2 = 22·3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24‐h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1·20 for AUC and 1·24 for urinary excretion. The effective half‐life for accumulation was estimated at about 10–11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the drug kinetics and excretion.
Biomimetic models for monooxygenases
Authors: Zbaida Shmuel , Kariv Rami
Published: October 2006

The microsomal mixed function oxidase system contains the cytochrome P‐450 oxidative drug metabolizing family of enzymes. The catalytic cycle of cytochrome P‐450 is believed to involve the formation of an active iron‐oxygen species which is responsible for oxygen transfer to the substrate. This assumption is supported by the fact that a number of peroxidative agents can replace NADPH, the reductase, and oxygen as co‐reactants in most oxidative reactions of microsomal cytochrome P‐450. We have found that a mixture of either ferrous or ferric ions with hydrogen peroxide (Fenton and Ruff reagents) can serve as biomimetic models for cytochrome P‐450 in hydroxylation, exposidation, sulfoxidation, and N‐demethylation of various drugs. The existance of an iron‐oxo active species in both Fenton and Ruff type reactions has been postulated and provides reaction cycles similar to those of cytochrome p‐450.

Other model systems for the hepatic hydroxylation and epoxidation using transition metal complexes with porphyrin are also discussed.

The present paper reviews the various biomimetic models of the heme cytochrome P‐450 and emphasizes their simulation of hepatic drug metabolism and their potential medical and industrial applications.
Pharmacokinetics and dose linearity testing of methylprednisolone phosphate
Authors: Möllmann Helmut , Rohdewald Peter , Barth Jürgen , Verho Matthi , Derendorf Hartmut
Published: October 2006

The pharmacokinetics of methylprednisolone and methylprednisolone phosphate were investigated after intravenous administration of methylprednisolone phosphate to six healthy subjects at seven different doses between 16 and 1000 mg. Plasma, urine, and saliva were analyzed for methylprednisolone and methylprednisolone phosphate. Furthermore, endogenous hydrocortisone was measured in plasma. No non‐linearity in the total body clearance of methylprednisolone phosphate or methylprednisolone could be detected. The average elimination half‐life for the prodrug was 3·7 min indicating rapid hydrolysis. After 15 min more than 90 per cent of the phosphate has been hydrolyzed. No prodrug could be detected in saliva; very little of the ester (average 0·9 per cent of the dose) was excreted unchanged into the urine. Methylprednisolone is formed rapidly. The total body clearance was 21 1h−1, the terminal half‐life 2·8 h. In the post‐distribution phase methylprednisolone levels in saliva went parallel to plasma levels. The mean saliva/plasma ratio was 0·22. An average of 5·2 per cent of the dose was eliminated into the urine in the form of methylprednisolone. Hydrocortisone suppression was dosedependent. For doses above 125 mg hydrocortisone levels were significantly lowered after 24 h. For doses above 500 mg the suppression was still significant after 48 h. The results indicate a rapid and predictable in vivo conversion of methylprednisolone phosphate to its active form methylprednisolone.
Absorption kinetics of cyclosporine in healthy volunteers
Authors: Gupta Suneel K. , Benet Leslie Z.
Published: October 2006

The absorption kinetics of cyclosporine were studied in eight healthy volunteers following oral and intravenous administration. Bioavailability of cyclosporine was observed to be 20±8 ± 5·5 per cent. Absorption of cyclosporine was found to be better described by first order processes rather than by a zero order process as previously reported.
A single and multiple dose pharmacokinetic and metabolism study of meclofenamate sodium
Authors: Koup J. R. , Tucker E. , Thomas D. J. , Kinkel A. W. , Sedman A. J. , Dyer R. , Sharoky M.
Published: October 2006

A single and multiple oral dose administration study of meclofenamate sodium (Meclomen®) was conducted in ten healthy male volunteers. An initial 300 mg oral dose on day I was followed by a 100 mg every 8 h dosage regimen on study days 4 through 18. Intensive plasma and urine sample collection was carried out over the first three study days, and for 120 h following administration of the final dose on day 18. Plasma and urine specimens were analyzed by a specific HPLC assay for unconjugated meclofenamic acid and metabolites I and II of meclofenamic acid before and after sample incubation with β‐glucuronidase.

Meclofenamic acid was rapidly absorbed following oral dose administration. Concentrations of meclofenamic acid existed primarily as unconjugated drug in plasma, with only a small amount present in the conjugated form. Meclofenamic acid was rapidly eliminated, with an elimination half‐life of approximately 1.3 h. This resulted in no detectable accumulation upon multiple dose administration. Metabolite I, which is one‐fifth as active as meclofenamic acid in in vitro inhibition of cyclooxygenase, was present in unconjugated form at steady state in concentrations approximately 50 per cent of those of meclofenamic acid, as unconjugated drug. The majority of metabolite I in plasma existed as glucuronide conjugate. Metabolite II, which is inactive, was present in very significant concentrations in unconjugated form. Plasma protein binding determinations conducted on meclofenamic acid and metabolite I indicated that the free fraction of metabolite I was 8·7 to 10·9 times higher than that of meclofenamic acid. When the lower activity and lower steady state concentrations, but higher free fraction, are considered, it would appear that metabolite I may contribute significantly to the in vivo inhibition of cyclooxygenase activity seen after administration of meclofenamic acid.
Effect of dietary fat content on the bioavailability of a sustained release quinidine gluconate tablet
Authors: Martinez M. N. , Pelsor F. R. , Shah V. P. , Skelly J. P. , Honigberg I. L. , Hemingway S. M. , Gallo J. M. , Kotzan J. A. , Zaman R. , Brown W. J. , Cliett S.
Published: October 2006

Quinidine gluconate 324 mg sustained release tablets (Quinaglute) was administered as a single dose to 15 healthy male subjects following an overnight fast, immediately following a high fat (HF) breakfast or immediately following a low fat (LF) breakfast. Serum samples were obtained over a 48 h period and analyzed for quinidine content using a high performance liquid chromatographic assay. Under the conditions of the study, both the rate and extent of quinidine bioavailability was significantly affected by food. The extent of bioavailability was statistically significantly greater (p<0·05) following both the HF and LF meals as compared to that in the fasted state. Rate of bioavailability was significantly enhanced following the LF meal as compared to that of the other two treatment groups. Although peak concentrations were greater and time to peak concentrations somewhat later following the HF meal versus those under fasting conditions, these differences were not statistically significant. In addition, the characteristics of the serum concentration‐time profile (as defined by the number, magnitude, and time of occurrence of the multiple absorption maxima) was unique for each of the three treatment groups. Possible mechanisms underlying these results are explored.
Absolute bioavailability of terbutaline from a CR‐granulate in asthmatic children
Authors: Fuglsang Gunver , Hertz Birgitte , Holm Eva Bettina , Borgström Lars
Published: October 2006

The study aimed at finding the absolute bioavailability of terbutaline of a newly developed CR‐granulate. Eight asthmatic children, aged 8–13 years, were given 3 mg of terbutaline as the CR‐granulate, concomitant with the intravenous administration of 0·100 mg of deuterium‐labelled terbutaline. The labelling of the intravenous dose made possible a separation, in the analytical step, of terbutaline originating from the intravenous and oral administration. Maximal plasma concentration, 8·7 (range: 4·9–15·2) nmoll−1, was reached after 4·7 (2·2–6·0) h. Absolute bioavailability was 10·8 (7·63–16·4) per cent. The parameter values were similar to those found after administration of terbutaline CR‐tablets to adults. The CR‐formulation is easily swallowed and can be dosed twice daily. Thus it should be a good alternative to elixir or plain tablets, dosed three times a day.
Dose dependent pharmacokinetics of N‐ACETYLCYSTEINE AFTER ORAL DOSING TO MAN
Authors: Borgström Lars , Kågedal Bertil
Published: October 2006

The pharmacokinetics after oral administration of 200, 600 or 1200 mg of N‐acetylcysteine (NAC) were studied in 10 healthy subjects. Normalized maximal plasma concentration was significantly higher after a 600 mg dose than after a 200 mg dose. Bioavailability of NAC significantly increased with increasing dose. Time for maximal plasma concentration also increased with increasing dose. The observations can be explained by a capacity‐limited presystemic elimination of NAC. In an extension of the study, 600 mg of NAC was given twice a day for 5 days and the plasma concentrations were followed after the morning dose on day 6. No differences in the pharmacokinetic parameters were observed in comparison with the single 600 mg dose. This indicates that the beneficial clinical effects observed after repeated dosing can not be ascribed to an accumulation of NAC in plasma.