bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractHigh 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

AbstractThe 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

AbstractThe 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

AbstractTissue 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

AbstractEleven 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

AbstractCimetidine 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

AbstractAsialofetuin‐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

AbstractA 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

AbstractThe 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

AbstractA 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

AbstractA 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

AbstractCefuroxime 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

AbstractThis 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

AbstractEtintidine 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

AbstractElevations 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

AbstractFive 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

AbstractA 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.