bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of prednisolone after high doses of prednisolone hemisuccinate
Authors: Derendorf H. , Rohdewald P. , Möllmann H. , Rehder J. , Barth J. , Neveling D.
Published: October 2006

Prednisolone in the form of its hemisuccinate was given intravenously in two different doses (1200 mg and 75 mg). Plasma levels of the ester and prednisolone were measured and pharmacokinetic parameters were calculated. The results indicate a dose‐dependency in the pharmacokinetics of both hemisuccinate and the free alcohol. For the high dose 8 per cent of the administered ester was found unchanged in the urine indicating incomplete conversion of the pro‐drug. Comparison with previous studies leads to the conclusion that prednisolone shows doubled non‐linear pharmacokinetics with higher total body clearance in the medium dose range than in the low and high dose range. Volume of distribution changes accordingly, but overall elimination rate remains remarkably constant. Saliva levels of prednisolone were low and agree reasonably well with calculated plasma concentrations of free, non‐proteinbound prednisolone. No prednisolone hemisuccinate was found in saliva.
Effects of phenobarbital steady state levels on antipyrine clearance and distribution in the rat
Authors: Pei Yuan‐Ying , Bialer Meir , Levy René H.
Published: October 2006

A group of 15 rats received two intravenous bolus doses of antipyrine (15 mg/kg) separated by a 57 hour infusion (with bolus dose) of phenobarbital. Phenobarbital bolus doses and infusion rates were based on a preliminary pharmacokinetic study (7 rats) and were varied to achieve a broad range of steady state levels. Antipyrine and phenobarbital blood levels were measured by high pressure liquid chromatography. Antipyrine kinetics obeyed first order monoexponential decay, and the parameters (clearance, volume, half‐life) were determined. Antipyrine clearance increased in all animals during phenobarbital infusions with a per cent increase ranging between 54·6 and 269 per cent. However, no significant correlation was found between the per cent increase in antipyrine clearance and phenobarbital concentration (r = 0·19). The volume of distribution of antipyrine increased in 14 of 15 animals with increases ranging between 7·7 and 45·8 per cent.
Evaluation of two new megestrol acetate tablet formulations in humans
Authors: Gaver R. C. , Pittman K. A. , Reilly C. M. , Goodson P. J. , Breault G. O. , Fenzl E.
Published: October 2006

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet (Megace®). The tablets were administered to 24 male subjects in a three‐way cross‐over study, balanced for sequence, with a week between administrations. The 40 mg tablets were administered q.i.d. at 08.00, 12.00, 18.00 and 22.00 h, while the 160 mg tablets were administered once at 08.00 h. Plasma samples were collected at appropriate times out to 96 h after administration and were analysed for megestrol acetate with a validated high performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2·5 to 2·8 h), the absorption rate constant was the same for each of the tablets. Relative to the 40 mg q.i.d. dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97 per cent and 118 per cent, respectively.
The pharmacokinetics of oral and intravenous prenalterol in young, healthy volunteers
Authors: Clarke A. F. , Jack D. B. , Kendall M. J. , Smith S. R.
Published: October 2006

The pharmacokinetics of prenalterol in healthy young volunteers after i.v. and oral dosing has been studied. There is evidence of non‐linearity following the i.v. dosing. Evidence of dose‐dependent pharmacokinetics following i.v. dosing has been obtained. The sustained‐release formulation is very effective: almost 12 h were needed to achieve 50 per cent of the total AUC.
The effect of administration of propranolol on the pharmacokinetics of isoxicam
Authors: Caillé G. , Larivière L. , Lacasse Y. , Vézina M. , Besner J. G.
Published: October 2006

In order to examine a potential interaction between isoxicam and propranolol, single 200 mg doses of isoxicam were administered to ten healthy male volunteers before and during treatment with propranolol, gradually attaining a dose of 80 mg t.i.d. for 11 days. The pharmacokinetic profiles of the isoxicam plasma concentration/time data obtained over 96 h following the doses of isoxicam before and during propranolol administration were compared. No significant change was found in any of the pharmacokinetic parameters determined. These results suggest that propranolol has no effect on the metabolic disposition of isoxicam.
Bioavailability of seven furosemide tablets in man
Authors: Straughn Arthur B. , Wood George C. , Raghow Gursharan , Meyer Marvin C.
Published: October 2006

A seven‐way crossover study was conducted in 14 healthy male volunteers to evaluate the relative bioavailability of seven different marketed 40 mg furosemide tablets. Each dose was administered as a single tablet after an overnight fast, and blood samples were obtained for 16 hours. Plasma was assayed by HPLC. There were no statistically significant differences among the seven products for the mean peak concentration (1·01–1·29 μg/ml), mean time of peak (1·2–2·1 h) or mean area under the plasma concentration‐time curves, which differed by less than 14 per cent. However, one product exhibited greater intersubject variability, and on this basis was considered inequivalent to the other six products.

Furosemide is a potent and widely used diuretic. Currently the United States Food and Drug Administration (USFDA) has granted approval to at least twelve manufacturers of 40 mg furosemide tablets, based in part on bioavailability data obtained in human subjects. In addition, the USFDA has granted an ‘AB’ therapeutic equivalence evaluation to each of these products.1 which is understood by many to indicate the therapeutic equivalence and interchangeability of these products.

The objective of the present investigation was to directly compare the bioavailability of seven 40 mg furosemide tablet products which had previously been approved by the Food and Drug Administration.
Limitations of the MANOVA of statistical moments in bioequivalence trials of drugs with slow elimination rate: A study with spironolactone
Authors: Concheiro A. , Llabres M. , Martinez R. , Vila J. L.
Published: October 2006

The capacity of the statistical moments for detecting bioavailability changes in bioequivalence studies of drugs with high disposition mean residence time (MRT) is analysed. Two bioavailability trials were carried out with spironolactone in which extent and rate of absorption were modified in a controlled way. The statistical analysis employed was a two‐way MANOVA of statistical moments of the urinary excretion profiles of canrenone. The results indicate a loss in the sensitivity of MRT for detecting changes in absorption rate as drug elimination rate decreases.
Bioavailability of cyanamide in fasted and unfasted rats
Authors: Obach R. , Valenti C. , Valles J. , Valles J. M. , Domenech J.
Published: October 2006

The pharmacokinetics of cyanamide after 35 mg kg−1 intravenous and oral administration to fasted and unfasted rats have been investigated. The plasma level are fitted well by a two‐compartment open model. The half‐life (t1/2β) of cyanamide in the rat was 1 hour and the plasma clearance (C1p) was 0.02 (1 kg−1) min−1. Food does not appear to modify the absolute bioavailability of cyanamide (F = 93.3 per cent fasted, F = 85.5 per cent unfasted), although it does retard drug absorption.
Bioequivalency and dose proportionality of three tableted promethazine products
Authors: Zaman R. , Honigberg I. L. , Francisco G. E. , Kotzan J. A. , Stewart J. T. , Brown W. J. , Shah V. P. , Pelsor F. R.
Published: October 2006

Data from a five‐way crossover study in human subjects using four talented promethazine products and a promethazine solution are presented. All products were administered as a single oral dose. The five objectives of the study were to investigate bioequivalency, to estimate dose proportionality at two dose levels, to establish validity of a reference production solution for future bioequivalency studies, to estimate intersubject variation, and to compare bioavailability/tablet dissolution data. Blood samples were collected at given intervals over a 24‐hour period and analysed for promethazine using an HPLC technique. Pharmacokinetic parameters were calculated using standard procedures and a two‐way analysis of variance (ANOVAR) was used to assess whether the differences were statistically significant. The AUC0→∞ data from the ANOVAR analysis showed that the 50 mg innovator and generic products and the 50 mg solution were not significantly different. However, the innovator product had a significantly lower Cmax and longer tmax than the solution. The generic product did not differ significantly from the solution. Promethazine was found to exhibit linear dose proportionality in the range and product studied. Intersubject variation was high for all parameters (23 to 63 per cent) and the in vivo and in vitro data showed a positive relationship.
Comparative physiological disposition of two nitrofuran anti‐microbial agents
Authors: Labaune J. P. , Moreau J. P. , Byrne R.
Published: October 2006

The physiological disposition of two nitrofuran derivatives used as antimicrobial agents for the treatment of acute infectious diarrhea was evaluated in humans and animals. Upon administration of a single oral dose (600mg) of nifurzide or nifuroxazide, no unchanged parent drug was detected in human blood or urine. In rats given 14C‐nifurzide and 14C‐nifuroxazide at a dose of 10mg kg−1, 5 per cent and 17 per cent of the dose of nifurzide and nifuroxazide, respectively, were excreted in urine over a 48‐hour period. None of this radioactivity was present as unchanged drug, indicating that renal excretion of both drugs occurs as metabolites. In the feces 20 per cent of the radioactivity recovered was associated with unchanged nifuroxazide as compared with 100 per cent for nifurzide. Whole body autoradiography using rats showed that after oral administration of 14C‐nifurzide and 14C‐nifuroxazide, most of the radioactivity remained in the gastrointestinal lumen.
Preparation and disposition of asialofetuin‐labelled liposome
Authors: Tsuchiya Seishi , Aramaki Yukihiko , Hara Toshifumi , Hosoi Kaoru , Okada Akira
Published: October 2006

A liposome labelled with asialofetuin(AF‐liposome) was prepared by the detergent dialysis method. Asialofetuin in the amount of 34–68 μg were imposed among the 1 μM of phospholipids constituting the outer surface of liposome. The AF‐liposome containing [14C]‐cholesterol in the lipid layer and [3H]‐sucrose in the aqueous layer was intravenously administered to rats. Both radioactivities were biphasically cleared from systemic circulation at rates faster than that of the fetuin‐labelled liposome. These radioactivities were recovered in the liver by about 90 per cent within 60 min, and per gram of tissue, were highest in this organ. In an in vitro experiment using isolated rat hepatocytes, the high affinity of the AF‐liposome toward hepatocytes was observed from scanning electron micrographs. Based on these findings, the AF‐liposome may possibly be stable in circulation and function as a carrier of encapsulated drugs to hepatocytes.
Plasma concentrations and bioavailability of propranolol by oral, rectal and intravenous administration in man
Authors: Cid Edison , Mella Fernando , Lucchini Leonardo , Cárcamo Martín , Monasterio José
Published: October 2006

Eight normal male volunteers received 80 mg doses of propranolol by the oral and rectal routes and 2·2 mg by intravenous administration in a crossover fashion. Plasma concentrations of propranolol were measured by a gas chromatographic method using an electron capture detector. Individual subject concentration–time data were analysed and results indicated that the data fit a two compartment model with first order absorption. An approximately two‐fold higher plasma propranolol concentration was observed after rectal administration as compared with oral dosing. Statistical analysis of the difference in the total AUCs indicates a significantly higher bioavailability of propranolol administered by the rectal route. The reduced bioavailability after oral administration indicates a substantial first pass effect but that it is possible to bypass the liver, at least partially, by giving the drug rectally to man.
Correlation between inhibitory effect on platelet aggregation and disposition of sulfinpyrazone and its metabolites in rabbits. Part I: Single dose study
Authors: Ritschel Wolfgang A. , Kuo Be‐Sheng
Published: October 2006

Simultaneous evaluation of inhibition of the sodium arachidonate‐induced platelet aggregation and drug disposition was studied in rabbits receiving single doses of sulfinpyrazone (SO) and its sulfide metabolite (S). The metabolism of SO was found to be interconversible with that of S. Due to the parallelism of disposition profiles, the observed concentration‐related inhibition not only strongly correlated with the much more potent sulfide, but also correlated with the p‐OH‐sulfide (OH‐S) or with a summation of two substances. Exaggeration of inhibition at 24–30h and rebound effect at 48h were found after the substances were administered. There may exist a circadian rhythm of platelet aggregation.
The bioavailability of oral nifedipine formulations: A statistical and simulation approach
Authors: Kozjek F. , Primozic S. , Mrhar A. , Karba R. , Raemsch K. D. , Janezic A.
Published: October 2006

The bioequivalence of three oral forms of nifedipine was assessed in a triple crossover study on 12 healthy volunteers. Single 10 mg dose was given and ten blood samples were drawn during the first 8 h after administration. Highly sensitive gas chromatographic method was used for the nifedipine assay. Pharmacokinetic parameters which describe bioavailability and general kinetic behaviour of the drug (AUC, Cmax, tmax, beta, MRT) were calculated from individual plasma profiles. They were subjected to statistical analysis (paired t‐test, Hauck's inverted t‐test, and Westlake's method of confidence intervals). Analogue‐hybrid simulation and identification was used to generate plasma profiles of nifedipine after single and multiple dosing. Averaged plasma concentrations were used for this purpose. The three formulations studied were bioequivalent in terms of the rate of absorption. The simulation proved to be an efficient tool to substitute in vivo multiple dosing studies for assessment of bioavailability. The specific statistical methods should be preferred in bioequivalence data evaluation due to their greater power and inclusion of extraneous bioequivalence limits interval. Despite the differences among the formulations studied, each one of them should be viewed according to its intended clinical use.
Method of residuals: Estimation of absorption and elimination rate constants having comparable values
Authors: Macheras P.
Published: October 2006

An equation was developed to be used with the method of residuals for the analysis of the linear one‐compartment open model. This equation can provide information about the magnitude of the ratio of rate constants, without assuming that the terminal phase reflects solely either an elimination or an absorption process, as must be done for the graphical techniques. It also enhanced the analytical power of the method of residuals in that it gave better estimates of the absorption rate constant when the latter and the elimination rate constant have comparable magnitudes.
Lack of effect of multiple doses of cimetidine on estimated hepatic blood flow
Authors: Grasela Dennis M. , Rocci Mario L. , Rotmensch Heschi H. , Vlasses Peter H.
Published: October 2006

Conflicting data exists regarding the effect of the H2‐receptor blocking agent cimetidine on hepatic blood flow (HBF). The variance in the results of these studies may be due in part to differences in the duration of cimetidine administration, the posture of the volunteers during their course of study, and the method used to estimate HBF. To assess the effects of chronic cimetidine (300 mg q.i.d. × 4 days) on estimated HBF while controlling posture (supine and standing), a double‐blind, placebo‐controlled, repeated measures study was performed in 9 healthy males. Indocyanine green (ICG) plasma clearance after an i.v. dose of 0.5 mg kg−1 was used to calculate HBF. ICG plasma concentrations were measured by HPLC. Compared to placebo treatment, cimetidine had no effect on mean (SD) estimated HBF (ml min−1 m−2) in either the supine (497 (64) vs 494 (80)) or the standing (443 (117) vs 404 (89)) posture. These data had a power > 0.8 to detect a treatment effect of 20 per cent. Standing produced a significant decrease in estimated HBF (496 (70) vs 424 (102); p < 0.01). In contrast to previous reports, chronic cimetidine treatment had no apparent effect on hepatic blood flow.
Prediction of drug distribution in vivo on the basis of in vitro binding data
Authors: Schuhmann G. , Fichtl B. , Kurz H.
Published: October 2006

For 11 drugs it was investigated whether tissue distribution in vivo can be predicted by use of binding data obtained in vitro. The selection of drugs represented a broad spectrum of physicochemical and pharmacokinetic properties thought to be important for distribution of drugs in vivo. The extent of binding to plasma and to tissue‐homogenates of rabbits was determined in vitro. The drug concentrations in plasma, liver, lungs, kidneys, and skeletal muscle of rabbits were determined in vivo after i.v. administration of the drug. The tissue‐plasma partition ratios measured in vivo were compared with the theoretical tissue‐plasma partition ratios calculated from the in vitro binding data.

For all drugs investigated the muscle‐plasma partition ratio could be reasonably well predicted by the in vitro binding data. In liver, lungs, and kidneys good agreement was found between measured and predicted tissue‐plasma ratio for anionic drugs; marked differences, however, were observed between measured and predicted tissue‐plasma ratios of lipophilic cationic drugs. A significant correlation was found between binding of drugs to muscle tissue in vitro and the volume of distribution of the unbound drug (Vf), opening the possibility to approximate Vf from in vitro binding studies with rabbit muscle tissue.
Definition of mean residence times in pharmacokinetics
Authors: Cutler David J.
Published: October 2006

A new definition of the mean residence time is proposed which includes the commonly used definition as a special case. The advantage of the new definition is that it applies for both linear and non‐linear systems. Some practical advantages which follow from the new definition are discussed. Procedures for using urinary excretion data in mean residence time estimation are discussed.
Pharmacokinetics of tiazofurin in dogs
Authors: Obeng E. K. , Vallner J. J. , Cadwallader D. E. , Tackett R. L.
Published: October 2006

The pharmacokinetics of total and free tiazofurin, an antineoplastic agent, was studied in healthy mongrel dogs following intravenous and oral administration of the drug. The free fraction of tiazofurin was obtained from plasma by an ultrafiltration technique using a micropartition system. Total and free tiazofurin levels were determined by a sensitive high performance liquid chromatographic method. The percentage of tiazofurin bound to plasma proteins remained constant at approximately 15 per cent following administration to healthy mongrel dogs. The mean pharmacokinetic parameters of elimination rate constant (K), effective half‐life (t1/2), mean residence time (MRT) and the time to reach peak plasma level (tmax—after oral administration) were 0.32 ± 0.04 h−1, 2.24 ± 0.25 h, 3.23 ± 0.36 h, and 1.78 ± 0.50 h, respectively. The apparent volume of distribution at steady state was 0.98 ± 0.30 I kg−1 and the plasma clearance was 5.24 ± 2.39 ml min−1 kg−1. About 90 per cent of tiazofurin was absorbed following oral administration. The pharmacokinetic parameters did not differ significantly between the total and free drug levels, indicating that the pharmacokinetics of total tiazofurin levels reflect those of the free tiazofurin in plasma.
Comparison of high pressure liquid chromatography and fluorescence polarization immunoassay to assess quinidine pharmacokinetics
Authors: Bottorff Michael B. , Lalonde Richard L. , Straughn Arthur B.
Published: October 2006

High pressure liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) were compared in a quinidine pharmacokinetic study. Six healthy male subjects received single oral doses of regular release (RR) quinidine sulfate, sustained release (SR) quinidine bisulfate and the same dose of the SR product with food (SR‐F). Serum was collected for 49 h after each dose and analysed for quinidine by HPLC and FPIA. Using HPLC, there were no statistically significant differences between dosing regimens with respect to area under the curve (AUC) or terminal rate constant (K). The RR dose resulted in a higher peak plasma concentration (Cp) and shorter time to peak (Tp) than either of the SR doses (p < 0.01). Food had no apparent effect on the bioavailability of the SR product. When using FPIA, food administration was found to increase the AUC for the SR product (p < 0.05) and all three dosage regimens resulted in a different Cp, and Tp (p < 0.001). When comparing all pharmacokinetic parameters determined by each assay, FPIA resulted in a significantly lower K (p < 0.01). Orthogonal regression of all serum quinidine concentrations showed that FPIA = 0.926 (HPLC) + 0.06 (r = 0.971, p < 0.001). Analysis of quinidine concentrations in different concentration ranges revealed that FPIA overestimated HPLC for concentrations <1 μg ml−1 (p < 0.001) and underestimated HPLC for concentrations > 2 μg ml−1 (p < 0.01). Although the use of FPIA is appropriate for quinidine therapeutic drug monitoring, HPLC is the preferred assay method for assessing pharmacokinetic parameters in single dose bioavailability studies.
Interpretation and estimates of mean residence time with statistical moment theory
Authors: Kasuya Yasuji , Hirayama Hiroki , Kubota Noriyoshi , Pang K. Sandy
Published: October 2006

The definitions of mean residence time of drug molecules in the body (MRT) from the literature are reviewed. A formal definition of MRT, based on excretion of drug molecules and amount of drug, a parameter which is independent of constancy of both clearance and volume of distribution, is introduced and compared to other existing definitions of MRTs, that is, MRT for the two‐compartment model, MRT for the stochastic model, and MRT based on amount in the body. The inherent assumptions of the methods for determining the various MRTs are discussed. Published information on coefficients and constants (Collier21) which describe a biexponential drug decay in the systemic circulation were utilized to illustrate the similarities and differences in MRTs. MRTs were calculated from theoretical relationships as well as estimated from simulated data based on equivalent conditions. The MRTs based on area under the moment curve/area under the curve (AUMC/AUC) for the two‐compartment model and AUC/C(0) for the stochastic model assume a constancy in clearance and in volume of distribution, respectively.
Steady‐state pharmacokinetics of metronidazole in Crohn's disease
Authors: Eradiri Okponanabofa , Jamali Fakhreddin , Thomson Alan B. R.
Published: October 2006

The pharmacokinetics of metronidazole (MTZ) were studied in six Crohn's disease patients after multiple oral daily doses of 250, 500, 750, and 1000 mg day−1 Pharmacokinetic indices were found to be independent of the dose administered. The half‐life, volume of distribution and oral clearance of metronidazole were 9.5 ± 2.1 h, 0.732 ± 0.0941 kg−1 and 0.921 ± 0.175 (ml min−1) kg−1 (mean ± SD), respectively. A strong linear correlation (r = 0.95) was found between the volume of distribution of MTZ and the patients' total body weight. The percentage of dose of metronidazole excreted in urine as the intact drug and metabolites as well as glucuronic acid conjugates ranged from 34.7 ± 7.4 to 58.9 ± 5.2. Both plasma and urine data exhibited very large inter‐patient variations. However, intra‐patient variations were negligible. Strong positive linear correlations were observed between the dose and the areas under the plasma concentration versus time curves, peak plasma concentrations as well as cumulative urinary excretion of the drug and its metabolites. It is concluded that in Crohn's disease, the pharmacokinetics of MTZ and its metabolites are linear and that the drug concentrations are dependent on the total body weight.
Physiological pharmacokinetics and pharmacodynamics of (±)‐verapamil in female rats
Authors: Todd Elizabeth L. , Abernethy Darrell R.
Published: October 2006

Tissue distribution and pharmacodynamics of verapamil were evaluated during steady state intravenous (i.v.) infusion and after single dose intraperitoneal (i.p.) drug administration to female Sprague–Dawley rats. In one group of rats, verapamil was infused to a steady state concentration at which time animals were killed. Verapamil‐induced decreases in mean arterial pressure (MAP) were monitored during infusion and correlated with concomitantly obtained plasma verapamil concentrations. Tissue (lung, liver, renal medulla, renal cortex, cardiac muscle, skeletal muscle, perirenal fat, brain stem, cerebral cortex, and cerebellum) and plasma samples were obtained immediately after animals were killed and verapamil and norverapamil concentrations determined. Another group of rats, after receiving i.p. verapamil, were killed at 1, 3, 5, 19, and 24 h. Elimination from each tissue evaluated was described by a first order process. Elimination half‐life of verapamil was similar among plasma and tissues evaluated (1.5 to 2.2 h). The per cent verapamil not bound to plasma proteins was concentration‐independent and similar between rats recieving i.p. (mean ± S.D.) (2.28 ± 0.72 per cent) and i.v. (2.08 ± 0.03 per cent) verapamil. MAP and verapamil concentration in plasma (r = 0.75; p < 0.01) and cardiac muscle (r = .0.82; p < 0.01) were inversely correlated in a highly significant fashion during both i.v. and i.p. drug administrations. The tissue‐to‐plasma distribution ratio for verapamil and norverapamil was similar among animals receiving i.p. verapamil at all points of sampling, suggesting distribution equilibrium had been achieved. After steady state i.v. infusion, both verapamil and norverapamil tissue: plasma concentration ratios were greater than after i.p. administration. Higher tissue: plasma verapamil concentration ratios after i.v. administration than after i.p. administration suggest either only a pseudoequilibrium is attained after i.p. administration or that determinants of tissue distribution of racemic verapamil differ with different routes of drug administration. In these studies, MAP provided a reasonable pharmacodynamic marker for verapamil tissue and plasma concentrations.
The effect of food on ciramadol bioavailability in normal subjects
Authors: Audet P. R. , Chiang S. , Maroli A , Locniskar A. , Morrison G.
Published: October 2006

Eleven healthy volunteers completed a study to compare the relative bioavailability to orally administered ciramadol in a fasting versus postprandial state. A single oral dose of 30 mg of ciramadol was administered on two separate occasions, 2 weeks apart, in a randomized crossover study. A mono‐ or biexponential pharmacokinetic equation with first‐order absorption was applied to analyse the serum data for each subject. Significant differences were found in peak time (tmax) and absorption time (tabs) whereas the mean AUCs for the two modes of administration were not significantly different. The relative bioavailability (F) of the drug when administered in the postprandial state with respect to the fasting state was 96 per cent. It is thus concluded that ingestion of food has no effect on the extent of absorption of ciramadol; however, food may alter its rate of absorption.
Effect of domperidone on cimetidine and ranitidine absorption in rabbits
Authors: Al‐Khamis Khalil I. , Kaka Juzar S. , Matar Kamal M.
Published: October 2006

Cimetidine and ranitidine absorption were studied after oral administration to rabbits, alone or in combination with oral and intravenous domperidone. 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 cimetidine and ranitidine administration. Assays of cimetidine and ranitidine in plasma samples were carried out using HPLC method. Domperidone overall significantly reduced the area under the plasma concentration‐time curve (AUC) by approximately 30 per cent for both drugs. However, domperidone had little effect on the maximum plasma concentration (Cmax), the time taken to reach the maximum plasma concentration (Tmax), and the elimination half‐life (t1/2) of cimetidine and ranitidine. The results suggest that domperidone affects the extent but not the rate of cimetidine and ranitidine absorption by enhancing gastric emptying.
Specific incorporation of asialofetuin‐labeled liposomes into hepatocytes through the action of galactose‐binding protein
Authors: Hara Toshifumi , Aramaki Yukihiko , Tsuchiya Seishi , Hosoi Kaoru , Okada Akira
Published: October 2006

Asialofetuin‐labelled liposomes (AF‐liposomes) having mean diameters of 0.13 μm ([S]) and 0.35 μm ([L]) were obtained by the subsequent extrusion method in combination with dialysis.

Intravenously administered AF‐liposomes [S] were rapidly cleared from the systemic circulation. By pre‐ and post‐treatment of the rats with free asialofetuin (AF), the rate of elimination decreased to that of non‐labelled liposomes (N‐liposomes) [S]. The liver uptake of AF‐liposomes [S] (60 per cent of dose in 30 min) was about twice that of N‐liposomes [S]. Forty‐seven per cent of the AF‐liposomes [S] incorporated into the liver were found in the parenchymal cell fraction as against 20 per cent in the non‐parenchymal cell fraction. In contrast, N‐liposomes [S] were taken up primarily by non‐parenchymal cells as was also the case for AF‐ or N‐liposomes [L]. Both the lipid and aqueous markers of AF‐liposomes [S] were detected in subcellular fractions of the liver, but their distribution was noted to change differently with the lapse of time.

Intravenously administered AF‐liposomes [S] were specifically recognized by galactose‐binding protein and underwent disruption in the cell after being taken up by hepatocytes. AF‐liposomes [S] may possibly be utilized to deliver drugs into hepatocytes.
Methodologies for the analysis of reduced and oxidized N‐acetylcysteine in biological systems
Authors: Cotgreave Ian A. , Moldéus Peter
Published: October 2006

A rapid and sensitive assay is described for both reduced and oxidized N‐acetylcysteine in biological matrices. Free, reduced N‐acetylcysteine is derivatized, along with any endogenous free thiols, in situ by treatment of the samples with the membrane‐permeable, thiol‐reactive agent monobromobimane. The N‐acetylcysteine‐monobromobimane adduct thus formed is analysed by high performance liquid chromatography with fluorescence detection. Oxidized N‐acetylcysteine is released from disulfides by in situ treatment of the samples with dithiothreitol, rendering the total N‐acetylcysteine content of the system available for derivatization and analysis. The conditions of derivatization ensured 100 per cent recovery of N‐acetylcysteine as the monobromobimane adduct, and calibration curves were linear over the range 0.1 μM to 1.0mM N‐acetylcysteine. The precision of the assay procedures was 97 per cent over this range. These assay procedures have been applied to studies of the pharmacokinetics of N‐acetylcysteine following single oral and intravenous administrations of the drug to a single human volunteer.
Disposition of a silicon‐containing amide, an inhibitor of acyl‐CoA: Cholesterol acyltransferase, in dog and rat
Authors: Tse F. L. S. , Jaffe J. M.
Published: October 2006

The pharmacokinetics of 3‐(decyldimethylsilyl)‐N‐[2‐(4‐methylphenyl)‐1‐phenylethyl]propanamide (DMPP), an inhibitor of acyl‐CoA:cholesterol acyltransferase, have been studied in the dog and the rat using 14C and 3H dual‐labelled drug. In both species, gastrointestinal absorption of DMPP was slow and incomplete. amounting to approximately 20 per cent of the oral dose given in corn oil. In the rat, use of PEG‐400, Tween 80, ethanol, and aqueous CMC as vehicles resulted in similar or lower absorption than corn oil. Absorbed DMPP was rapidly and extensively distributed to body tissues. Data from the rat showed highest concentrations of radioactivity in the liver and spleen, while concentrations in the adrenals and lung also markedly exceeded circulating radioactivity levels. In both dog and rat, DMPP was completely metabolized prior to excretion. The routes of biotransformation involved hydrolysis of the amide bond, oxidation of the phenyl ring, and degradation of the decyldimethylsilyl propanoyl moiety. The metabolites of DMPP were excreted slowly, predominantly in the faeces. The elimination half‐life of 14C was 105 h in the dog and 83h in the rat, while that of 3H was approximately 32h in both species.
Development of a standard, freeze‐dried serum containing the drugs assayed most often in French hospitals
Authors: Prognon P. , Pradier F. , Chevallier A. , Montagnier C. , Postaire E. , Darbord J. C. , Pradeau D.
Published: October 2006

A quality control program for the therapeutic drug monitoring methodology used to determine serum levels of the fourteen drugs assayed most frequently by French hospital laboratories is described. The program has been adopted by the Societé Française de Biologie Clinique (SFBC), which provides participating laboratories with a statistical analysis of the performance data. The control samples developed for the program are prepared by spiking calf serum with, in one case, phenobarbital, phenytoin, carbamazepine, sodium valproate, amikacin, lithium carbonate, digitoxin and hydroquinidine, and, in the other case, caffeine, quinidine, digoxin, isoniazid and gentamycin.

After freeze‐drying the spiked serum, the drugs were shown to be stable for at least a year when stored at −20°, +4° and +22°; at the end of this time, the samples were pathogen free. For checking therapeutic drug monitoring methods, the freeze‐dried serum is diluted with distilled water (10 ml); these solutions are chemically stable, and remain pathogen‐free, when stored in stoppered glass tubes at −20° or +4° for 4 weeks.
HPLC determination of indalpine and its major metabolite in human plasma and a pharmacokinetic application
Authors: Toupin L. , Caillé G. , Vézina M. , Demontigny C. , Tawashi M.
Published: October 2006

A high‐performance liquid chromatographic method using a fluorometric detector was developed for the determination of plasma concentrations of the antidepressant indalpine (I) and its major metabolite 4‐[2‐(3‐indolyl)ethyl]‐2‐piperidinone (PK). the same procedure was used to measure, in urine, levels of I and of the metabolite, either conjugated or unconjugated. The sensitivity of the assay is 5 ng ml−1 of plasma or urine for both I and PK. Mean recoveries from plasma for PK, I, and the internal standard (quinine sulfate) were 86.4, 86.8, and 88.5 per cent, respectively. Mean recovery from urine for I was 82.5%. This method was used to establish the pharmacokinetic profiles of I and PK following a single oral administration of I (100 mg) in 8 healthy volunteers. Peak plasma concentrations for I and PK were obtained in an average time of 2.1 and 2.6 h (tmax), respectively. The mean absorption t½ of I was 0.8 h, the mean Vda 8781 and the mean clearance 581 h−1. The mean t½ for I and PK was 10.4 and 11.9 h, respectively. In a 12 h urine collection 3 per cent of I was excreted unchanged. No conjugated or unconjugated metabolite was found in urine samples. This method was also used to determine plasma levels 10 h post‐dose (50 mg t.i.d.) during chronic oral administration in 20 hospitalized patients. Mean plasma concentrations of I and PK post‐dose were 116 ng ml−1 and 43 ng ml−1, respectively.
Effect of dose and food on the bioavailability of cefuroxime axetil
Authors: Finn A. , Straughn A. , Meyer M. , Chubb J.
Published: October 2006

Cefuroxime axetil is an ester pro‐drug which permits the oral administration of cefuroxime. This study was designed to evaluate the dose proportionality of four different doses administered after a meal and to determine the absolute bioavailability of cefuroxime axetil administered with and without food. The study was a six‐way randomized crossover trial in 12 normal male volunteers. Subjects received an intravenous dose of cefuroxime (500 mg) and five oral doses of cefuroxime axetil (125, 250, 500‐twice, 1000 mg). The intravenous dose and one of the 500 mg doses was administered after an overnight fast. The other four oral doses were administered after a standard meal. Blood samples were collected prior to each dose and serially for 12 h after the dose. Urine was collected for 24 h. Plasma and urine samples were analysed for cefuroxime by high pressure liquid chromatography. There was a linear relationship between the fed dose and both the area under the plasma concentration time curve (r2 = 0.958) and the peak plasma concentration (r2 = 0.943). Based on a comparison of the AUC for the oral and intravenous data, 36 per cent of the fasting and 52 per cent of the fed 500 mg doses were absorbed. The mean peak plasma concentration was 43 per cent greater after the fed dose than the fasting dose. A plot of the mean fraction of unabsorbed drug versus time reveals that absorption is an apparent zero order process from 0.5 to 3 h after dosing.
Ophthalmic bioequivalence of steroid/antibiotic combination formulations
Authors: Schoenwald R. D. , Harris R. G. , Turner D. , Knowles W. , Chien D.‐S.
Published: October 2006

This study compared the relative ocular bioavailability in rabbits of the antibiotic/steroid combination of 0.3 per cent tobramycin and 0.1 per cent fluorometholone acetate to each of the two single‐entity products. Two separate studies were conducted, one measuring fluorometholone acetate in cornea and aqueous humour through 240 min and the other measuring tobramycin in the cornea through 120 min.

The results for fluorometholone acetate show that the combination product is 15 percent higher in AUC for the cornea than the single‐entity product (0.05<p<0.1). However, the combination product is only 4.4 per cent higher in AUC when aqueous humour levels are compared (N.S.). The single‐entity fluorometholone acetate ointment yielded cornea and aqueous humour levels which were 20 per cent (p < 0.01) and 6 per cent (N.S.) higher in AUC than the same tissues measured after topical instillation of the suspension. Statistical treatment of the data indicated that the suspension and ointment products, were bioequivalent with respect to fluorometholone acetate in aqueous humour, but not with respect to corneal concentrations.

Tobramycin was measured in the cornea following instillation of either the single‐entity solution or the combination suspension. Per cent bound (tobramycin to rabbit antibodies determined in vitro from the radioimmunoassay results) was used for statistical analyses of all group means and standard errors. The results indicated that the products were bioinequivalent.
Etintidine‐theophylline interaction study in humans
Authors: Huang Shiew‐Mei , Weintraub Howard S. , Marriott Thomas B. , Marinan Barbara , Abels Robert , Leese Phillip T.
Published: October 2006

Etintidine HCl is a potent H2‐blocker. The effect of clinical doses of etintidine on the disposition of theophylline was investigated in 10 male volunteers.

This was a double‐blind, two‐way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of theophylline elixir (5 mg/kg) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 h following the administration of theophylline. Plasma theophylline levels were analysed by HPLC.

Theophylline was rapidly absorbed following oral administration of the theophylline elixir to both the placebo and etintidine treatment groups. Comparison of the pharmacokinetic parameters of theophylline between the etintidine and the placebo groups indicates that while etintidine did not significantly (p > 0.05) affect the apparent Cmax (11.1 vs 10.0 μg ml−1) and Tmax (1.7 vs 1.4 h) values of theophylline, etintidine significantly reduced the oral clearance (0.0200 vs 0.0564 1kg−1 h−1, p = 0.000006) and prolonged the elimination half‐life (16.8 vs 6.0 h) of theophylline. The data indicate that etintidine, like cimetidine, extended the elimination of theophylline in humans.
Effect of cimetidine on quinidine bioavailability
Authors: Mackichan Janis J. , Boudoulas Harisios , Schaal Stephen F.
Published: October 2006

Elevations in quinidine steady‐state serum concentrations have been reported in patients who received cimetidine concurrently.1,2 Studies in normal volunteers3,4 have shown that areas under the serum concentration‐time curve of orally administered quinidine are higher when quinidine is given during chronic cimetidine therapy as compared to under control conditions. The mechanism for this interaction is generally ascribed to decreased hepatic clearance as a consequence of enzyme inhibition. In this study, we show that cimetidine also decreases the bioavailable fraction of quinidine.
Pseudoephedrine absorption from controlled release formulations: Absorption rate constant estimation methods
Authors: Graves David A. , Rotenberg Keith S.
Published: October 2006

Five methods of absorption rate (Ka) estimation were compared using data from a previously reported bioavailability study: Wagner‐Nelson (WN), asymptotic WN (AWN), the Hendeles‐Weinberger modification of the WN (HW), nonlinear regression performed on plasma concentration vs time data with fixed elimination rates (NL), and nonlinear regression performed on the cumulative sum of AUCs obtained during WN analysis (AUCNL). The maximum plasma concentration (Cmax) and the time at which Cmax occurred (Tmax) were predicted with each method's respective Ka's, and these were compared to observed values. The WN and HW were consistently biased in their predictions of Cmax and Tmax, providing slower Ka's than any of the other methods. AWN could only be used for the reference treatment. Both NL and AUCNL provided unbiased estimations, but AUCNL had a high level of imprecision. With this set of data, only NL was an acceptable method for accurately estimating Ka.
The absorption of sustained‐release methylphenidate formulations compared to an immediate‐release formulation
Authors: Patrick Kennerly S. , Straughn Arthur B. , Jarvi Eric J. , Breese George R. , Meyer Marvin C.
Published: October 2006

A crossover study in 18 subjects evaluated the plasma concentration–time profile of two different 20 mg sustained‐release (SR) methylphenidate (MPH) tablets administered before breakfast, compared to a 10 mg immediate‐release (IR) tablet administered before breakfast and again 5 h later, before lunch. Plasma MPH concentrations were determined using a sensitive and precise gas chromatography–mass spectrometry method, incorporating a deuterated internal standard. The mean peak MPH concentration was 6.4 ng ml−1 for the IR product versus 4·6 ng ml−1 and 4·8 ng ml−1 for the two SR formulations. Peak concentrations occurred at 3·3 h after dosing with the SR products, compared to 1·5 h after the first dose of the IR product. The extent of absorption for the three products, as determined from areas under the plasma concentration‐time curves, were within 5 per cent of each other. There was no significant difference in rate or extent of absorption between the two SR formulations.
Single oral dose proportionality pharmacokinetics of almitrine bismesylate in humans
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 single‐blind study was conducted in 10 healthy male subjects. Each subject was tested with four single oral doses of capsules containing 25, 50, 100, 200mg almitrine bismesylate and one dose of placebo. Blood samples were drawn as a function of time and the concentration of almitrine in plasma was determined by gas chromatography utilizing nitrogen‐phosphorus detection. Linear regression analysis of the data suggested that a deviation from linearity existed between the area under the plasma concentration time curves and the dose (R = 0·96). Linear analysis of the individual data indicates that a slight negative deviation from linearity is apparent for the 200mg dose, The same trend was observed for the mean maximum almitrine plasma concentration, Cmax, which ranged from 38·9 ± 11·8 to 286·2 ± 99·1 ngml−1 for the 25 and 200mg dose, respectively. The time to peak was relatively constant regardless of the administered dose and ranged from 2·4 ± 0·5h to 2·8 ± 0·8h. Good agreement was obtained between the observed bioavailability parameters and those predicted from the nonlinear fit of the data. Further kinetic analysis of the data revealed mean total body clearance over fraction of dose absorbed ranging from 268·2 ± 132·8 to 436·4 ± 191·4 ml min−1 for doses 50 and 200mg, respectively.
Evidence of a specialized transport mechanism for the intestinal absorption of baclofen
Authors: Merino M. , Peris‐Ribera J. E. , Torres‐Molina F. , Sánchez‐Picó A. , Garćia‐Carbonell M. C. , Casabó V. G. , Martín‐Villodre A. , Plá‐Delfina J. M.
Published: October 2006

Absorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats in situ, is shown to be a specialized transport mechanism obeying Michaelis‐Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis‐Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yielded Vm and Km values of 12·0mgh−1 and 8·0mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but comparable absorption rates were found in the proximal and distal segments of the small intestine, whereas in colon, drug absorption was negligible. Baclofen transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. If these results were extrapolated to humans, they would explain the excellent bioavailability profiles reported for baclofen at normal doses in spite of its physicochemical properties, which do not favour passive diffusion. Based on the same principle, the administration of usual doses at shorter time intervals could be recommended, instead of high, when higher plasma levels at steady‐state are needed. On the other hand, more than 8‐h sustainedrelease preparations of baclofen should, probably, be avoided.