bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of basic drugs on the hepatic uptake of ouabain by sinusoidal plasma membrane vesicles isolated from rat liver
Authors: Okudaira Kazuho , Yachi Kiyoto , Sawada Yasufumi , Sugiyama Yuichi , Iga Tatsuji , Hanano Manabu 
Published: October 2006

AbstractAlthough antiarrhythmic drugs are used to treat digitalis‐induced cardiac disorders, some of these drugs have been reported to increase the serum digoxin concentration in patients, causing the severe side‐effects. We have previously shown that many basic drugs including antiarrhythmic drugs inhibited the hepatic uptake of cardiac glycosides into isolated rat hepatocytes, which could be a cause for the increased serum digoxin concentration. The present study was designed to examine the mechanism of this inhibition using isolated rat sinusoidal plasma membrane vesicles. The effect of nine basic drugs (dipyridamole, nifedipine, verapamil, chlorpromazine, lidocaine, quinidine, ajmaline, disopyramide, and propranolol) on the uptake of ouabain was studied. Quinidine reduced the initial uptake rate of ouabain (30 s) while it did not change the uptake of ouabain in an equilibrium condition (30 min). Other basic drugs, such as verapamil, dipyridamole, and nifedipine also significantly reduced the initial uptake rate of ouabain. These basic drugs had no effect on the membrane fluidity. The inhibitory effects on the vesicular uptake were significantly correlated with the inhibitory effects on ouabain uptake by the isolated rat hepatocytes. These findings may suggest that the mechanism of the inhibition involves the inhibition of the transport process via the sinusoidal plasma membrane.
Drugs and the liver. Part III: Ageing of the liver and the metabolism of drugs
Authors: Woodhouse Ken 
Published: October 2006

AbstractThe clearance of many drugs by the liver is reduced in the elderly, and this accounts, at least in part, for the greater frequency of adverse drug reactions in this population.Ageing in experimental animals is accompanied by a decline in the activities of certain microsomal monooxygenase enzymes; this has been said to be the reason for decreased drug elimination. However, recent data suggests that this is probably not the case in humans. Reduced size and blood flow are important features of the ageing liver, and probably account for most of the age‐related changes in drug metabolism. Major decrements in hepatic function do occur in frail elderly individuals, although the mechanisms underlying this are at present unclear.Future studies of drug metabolism and ageing must carefully define patient groups to allow full interpretation of data.
Effect of indomethacin on the pharmacokinetics of methotrexate in rabbits
Authors: Najjar Tawfeeg A. O. , Morad Abdel Rehim M. , Khan Rao Muzaffar A. 
Published: October 2006

AbstractThe interaction between indomethacin (IND) and methotrexate (MTX) was investigated in rabbits. The study was designed so as to evaluate the effect of IND (1 mg h−1) during a continuous MTX infusion (1·2 mg kg−1) over 240 min. IND was injected i.v. at hourly intervals after a steady state MTX concentration had been established. Plasma MTX concentration before and after IND did not differ significantly (p>0·05). The elimination half‐life (t1/2β) calculated during the washout interval (mean ± SD) was 47·4 ± 21·5 min which is close to that calculated in a reference group of rabbits. This excludes the possibility of delayed elimination as responsible for this toxicity. The toxicity of this combination was confirmed despite the absence of significant pharmacokinetic changes. It is possible that the toxic interaction was caused by enhanced cytotoxic effect of MTX.
Effect of food and relative bioavailability following single doses of diclofenac 150mg hydrogel bead (HGB) capsules in healthy humans
Authors: Thakker K. M. , Mangat S. , Wagner W. , Castellana J. , Kochak G. M. 
Published: October 2006

AbstractThe effect of food on the bioavailabilty of diclofenac from a 150mg diclofenac hydrogel bead (HGB) capsule was evaluated in 12 healthy male subjects in a fed and fasted state. Additionally, the fasting bioavailability of diclofenac from a 150mg diclofenac HGB capsule relative to diclofenac sodium in buffered aqueous solution was evaluated in these same 12 subjects. The study was designed as an open‐label, randomized, single‐dose, 3×3 Latin‐square crossover trial balanced for residual effects. A 2‐week washout period was maintained between treatments. Blood samples were collected at frequent intervals over a 24‐h period with plasma being separated and analyzed for diclofenac using a validated HPLC method.The administration of the 150mg diclofenac HGB capsule dose within 30 min following a standardized breakfast minimally affected the bioavailability of diclofenac relative to administration under fasted conditions (7 per cent decrease in AUC(0‐24), p>0·05). There was, however, a 38 per cent decrease (p<0·05) in the Cmax and a three‐fold increase (p<0·05) in Tmax for the fed HGB capsule administration.Under fasted conditions, significant differences in mean pharmacokinetic parameters were found between the 150mg diclofenac HGB capsule and diclofenac sodium in buffered aqueous solution. The extent of availability of diclofenac from the HGB capsule was only 59 per cent relative to that from the solution (p<0·05). There was a 92 per cent decrease in the maximum plasma diclofenac concentration (Cmax, p<0·05) and an eight‐fold increase (p<0·05) in the median time required to reach this maximum level (Tmax) following HGB capsule administration.In conclusion, post‐prandial administration of the 150mg diclofenac HGB capsule resulted in a minimal decrease in bioavailability. The oral bioavailability of the diclofenac sodium in 150 mg diclofenac HGB capsules is significantly decreased relative to that of diclofenac sodium in solution.
‘In vitro’ action of histamine and cimetidine on amylase secretion in the rat pancreas
Authors: Murillo Luis Jiménez , Torre‐Cisneros Julián , Blanco‐Molina Angeles , López‐Miranda José , de la Puebla Rafael Angel Fernández , Pérez‐Jiménez Francisco 
Published: October 2006

AbstractWe report here the effect of histamine on amylase secretion in isolated lobules from the rat pancreas. Different concentrations of histamine increased amylase secretion, while the stimulatory effect was reduced by cimetidine although not by chlorpheniramine. These findings suggest that pancreatic lobules have H2 receptors. On the other hand, bethanechol induced a stimulatory effect on pancreatic lobules that was inhibited by cimetidine. Vibrio cholerae toxin stimulated amylase secretion, but this effect was not reduced by cimetidine. Cimetidine may thus block the stimulated amylase secretion interfering with the Ca2+ messenger system.
Prediction of the volume of distribution of 7‐hydroxycoumarin in man from in vitro and ex vivo data obtained in rat
Authors: Ritschel W. A. , Johnson R. D. , Vachharajani N. N. , Hussain A. S. 
Published: October 2006

AbstractThe essential parameter to estimate the first dose size of a drug in man is the volume of distribution. For a drug that has never been used in man before, estimates of the volume of distribution can only be obtained from animals and in vitro data. The purpose of this study was to compare various approaches presented in the literature for predicting the volume of distribution at steady state (VSS) and the terminal phase volume of distribution (Vdβ) in man. A lipophilic active metabolite of coumarin, 7‐hydroxycoumarin (7OHC), was selected for this investigation. This compound is extensively metabolized in both the central and peripheral compartments. Of the six methods evaluated, only an empirical allometric approach yielded a reasonable estimate of VSS. All methods underestimated VSS and none of the applicable methods were able to predict Vdβ. The reason for this discrepancy may be due to the fact that the calculation of Kss in man was done assuming elimination from the central compartment.
Influence of probenecid and paracetamol (acetaminophen) on zidovudine glucuronidation in human liver in vitro
Authors: Kamali F. , Rawlins M. D. 
Published: October 2006

AbstractThe effects of probenecid and paracetamol on zidovudine glucuronidation were investigated, in vitro, using human liver microsomal preparations. The presence of probenecid in the incubation medium significantly reduced the maximum reaction velocity for zidovudine glucuronide formation by more than 60 per cent, and the Km was reduced by 47 per cent, suggesting an uncompetitive inhibition of zidovudine glucuronidation. In contrast, paracetamol had no significant effect on zidovudine glucuronidation. The maximum reaction velocity for zidovudine glucuronide formation and the Km were unchanged when paracetamol (5 mM) was present in the incubation medium. The effects of probenecid and paracetamol on zidovudine metabolism in vitro correlates closely with those observed in vivo. The in vitro system of human liver microsomes may have a useful role in predicting the possible interaction of other drugs with zidovudine metabolism.
Pharmacokinetics and metabolism of codeine in humans
Authors: Vree Tom B. , Wissen Corrien P. W. G. M. Verwey‐Van 
Published: October 2006

AbstractCodeine (30 mg phosphate) was metabolized by eight human volunteers to the following six metabolites: codeine‐6‐glucuronide 81·0 ± 9·3 per cent, norcodeine 2·16 ± 1·44 per cent, morphine 0·56 ± 0·39 per cent, morphine‐3‐glucuronide 2·10 ± 1·24 per cent, morphine‐6‐glucuronide 0·80 ± 0·63 per cent, and normorphine 2·44 ± 2·42 per cent. Two out of eight volunteers were unable to O‐dealkylate codeine into morphine and lack therefore the cytochrome P450 IID6 isoenzyme. The half‐life of codeine was 1·47 ± 0·32 h, that of codeine‐6‐glucuronide 2·75 ± 0·79 h, and that of morphine‐3‐glucuronide 1·71 ± 0·51 h. The systemic clearance of codeine was 2280 ± 840 ml min−1, the renal clearance of codeine was 93·8 ± 29·8 ml min−1, and that of codeine‐6‐glucuronide was 122 ± 39·2 ml min−1. The plasma AUC of codeine‐6‐glucuronide is approximately 10 times higher than that of codeine. Protein binding of codeine and codeine‐6‐glucuronide in vivo was 56·1 ± 2·5 per cent and 34·0 ± 3·6 per cent, respectively. The in vitro protein binding of norcodeine was 23·5 ± 2·9 per cent; of morphine, 46·5 ± 2·4 per cent; of normorphine, 23·5 ± 3·5 per cent; of morphine‐3‐glucuronide, 27·0 · 0·8 per cent; and of morphine‐6‐glucuronide, 36·7 ± 3·8 per cent.
Extended least squares curve fitting: A comparison of SIPHAR and MKMODEL
Authors: Cockshott Ian D. , Haywood John 
Published: October 2006

AbstractSIPHAR and MKMODEL in their extended least squares modes have been compared when fitting a triexponential declining function to simulated data. The data were simulated on SAS incorporating normally distributed random error, having coefficients of variation (CV) of 5, 10, 15, and 25 per cent. At each error level 100 data sets, consisting of 21 data pairs, were simulated. Non‐parametric tests were used to compare the accuracy and precision of the estimates produced by the packages. The comparison was repeated with two different sets of exponent values incorporating error at the 15 per cent level. MKMODEL was also compared to ELSFIT and ELSMOS at the same error level. SIPHAR was consistently less accurate and less precise than MKMODEL in estimating the structural model parameters. SIPHAR was also sensitive to the concentration units used for the input data. Estimates of the variance model power produced by SIPHAR were very variable while those from MKMODEL covered a much tighter range. For both packages there was generally a linear increase in the CV on each mean parameter estimate with increase in the CV on the error model. Good agreement was observed between MKMODEL, ELSFIT, and ELSMOS. The presence of an additive constant in the variance model used in SIPHAR was shown to be responsible for its poorer accuracy and precision.
Bioavailability of lithium from lithium citrate syrup versus conventional lithium carbonate tablets
Authors: Guelen P. J. M. , Janssen T. J. , de Witte T. C. M. , Vree T. B. , Benson K. 
Published: October 2006

AbstractThe bioavailability of lithium citrate syrup was compared with that of regular lithium carbonate tablets in 18 healthy male human volunteers. Blood samples were collected up to 48 h after dosing. Lithium serum concentrations were determined by means of AAS. The absorption rate following oral administration of the syrup was greater (tmax 0·8 h) than following administration of regular tablets (tmax 1·4 h). Maximum lithium serum concentrations, however, were only about 10 per cent higher after syrup dosing and serum concentrations resulting from syrup and tablets were almost superimposable from 2 h after dosing. The terminal half‐life of lithium was found to be 22 h after syrup as well as after tablet dosing. No side‐effects were observed during the study. The bioavailability of lithium from syrup relative to tablets was found to be bioequivalent with respect to the maximum lithium serum concentration and the extent of drug absorption (AUC).
Effect of congestive heart failure on clentiazem pharmacokinetics in a dog model
Authors: K.‐Laflamme Annik , Caillé Gilles , Cardinal René , Croteau Daniel , Lamoureux Claudette , Lambert Chantal 
Published: October 2006

AbstractClentiazem, 8‐chloro diltiazem, is a calcium channel blocker currently undergoing evaluation for the treatment of stable angina and hypertension. As patients with ischaemic disorders often present some degree of heart failure, the aim of this study was to investigate the effect of congestive heart failure on clentiazem (200 μg kg−1, i.v. bolus) pharmacokinetics in a canine model. Congestive heart failure was induced in six dogs by rapid ventricular pacing (240 beats min−1) for 3–5 weeks. Clentiazem pharmacokinetics was studied in each dog under the control condition and after the development of clinical signs of heart failure (ascites, dyspnea, fatigue). Blood samples were collected up to 480 min post‐dose. Clentiazem plasma concentrations were determined by high performance liquid chromatography. The area under the plasma concentration versus time curves (AUC0−∞) was significantly increased in congestive heart failure dogs (8·8 ± 1·6 vs 21·8 ± 1·4 μg min ml−1) (mean ± SEM). These changes were related to a reduction of the volume of distribution of the central compartment (0·9 ± 0·1 vs 0·2 ± 0·1 1kg−1) and total body clearance (1·9 ± 0·4 vs 0·7 ± 0·2 1h−1 kg−1). It is concluded that, in our model, congestive heart failure significantly modifies clentiazem disposition. These results suggest that caution should be exercised when clentiazem is given to patients with a low ejection fraction and a compromised cardiac function. Reduced loading and maintenance doses might be recommended in patients with severe congestive heart failure.
The effects of chronic oral diltiazem and cimetidine dosing on the pharmacokinetics and negative dromotropic action of intravenous and oral diltiazem in the dog
Authors: Maskasame Chaiyasit , Lankford Susan , Bai Stephen A. 
Published: October 2006

AbstractThe kinetics and negative dromotropic action of intravenous (1 mg kg−1) and oral (5 mg kg−1) diltiazem were studied in dogs after acute doses, after treatment for 3 days with oral diltiazem (5 mg kg−1, t.i.d.), and after 3 days' treatment with oral diltiazem (5 mg kg−1 t.i.d.) and cimetidine (200 mg t.i.d.). Plasma concentrations of diltiazem and two of its metabolites, desacetyldiltiazem and desmethyldiltiazem were measured by HPLC. Chronic oral dosing significantly lowered both the systemic and oral clearance of diltiazem, with no changes in either the volume of distribution or blood binding of diltiazem. Cimetidine treatment resulted in a significant reduction in diltiazem oral clearance from chronic control with no effect on its systemic clearance. The AUCs of both metabolites increased by greater than threefold from acute to chronic oral dosing; however, the ratio of each metabolite's AUC to that of diltiazem AUC was not significantly altered. Cimetidine treatment significantly lowered these ratios. The negative dromotropic potency of diltiazem after the acute oral dose was three times greater than that after intravenous or chronic control dosing. Cimetidine treatment resulted in further lowering chronic oral diltiazem potency. These data indicate that the disposition and negative dromotropic action of diltiazem is dependent both on the route of administration and the duration of treatment, and can be altered by co‐administration with cimetidine.
Simultaneous monitoring of bemoradan pharmacokinetics and hemodynamics in mongrel dogs
Authors: Huang Shiew‐Mei , Falotico Robert , Haertlein Barbara , Smith Ian L. 
Published: October 2006

AbstractThis study was designed to determine the relationship between the hemodynamic responses to bemoradan, a novel cardiotonic agent, and its plasma levels after single administration of an oral dose or a 15 minute i.v. infusion to mongrel dogs, and to demonstrate that the clinical capsule formulation of bemoradan elicits a pharmacological response in the dog. Four conscious, instrumented mongrel dogs received each of four bemoradan treatments (30μg kg−1 i.v., 100μ kg−1 i.v., 100μ kg−1 suspension p.o., or 1 mg capsule p.o.) in a Latin square cross‐over design. Plasma levels of bemoradan up to 24 h post‐dosing were determined by HPLC. Cardiac contractility (dP/dt), heart rate, and arterial blood pressure were continuously monitored for 8 h and again at 24 h. Results of the study indicate that there was a significant correlation between bemoradan plasma levels and dP/dt. The 1 mg clinical capsule formulation was well absorbed when compared to an oral suspension and an i.v. dose. Peak increases in dP/dt of 64 per cent at 15 min for the suspension and 53 per cent at 1 h for the capsule were observed.
Pharmacokinetics of alfuzosin after single oral administration to healthy volunteers, of three different doses
Authors: Salva P. , Bianchetti G. , Morselli P. , Garcia‐Teresa G. , Costa J. 
Published: October 2006

AbstractThe aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2·5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2β) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1–5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2·5, and 5 mg were, respectively: tmax (h) 1·5±0·3, 1·1±0·2, 1·3±0·1; Cmax (ng ml−1) 2·6±0·3, 9·4±1·2, 13·5±1·0; AUC (ng ml−1 h) 17·7±2·9, 51·7±7·1, 99·0±14·1; t1/2 (h) 3·7±0·4, 3·9±0·2, 3·8±0·3. Cmax (corrected by the dose) obtained after 2·5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2·5 mg and 4 volunteers of 12 after 5 mg.
Disposition kinetics of 7,12‐dimethylbenz(a)anthracene in rats
Authors: Niazi Sarfaraz K. , Hussain Musarrat 
Published: October 2006

AbstractOne of the most potent carcinogens is 7,12‐dimethylbenz(a)anthracene (7,12‐DMBA), which is used routinely to conduct studies to evaluate carcinogen inhibitors. Its pharmacokinetics have not been reported in the literature. In view of its significant effects on drug metabolizing enzymes and clearance mechanisms, it is important to know its disposition characteristics. In this study, we monitored the disposition characteristics of 7,12‐DMBA in rats as a function of dose range commonly used in carcinogenesis studies. A mean residence time of 40–55 min was observed; the total body clearance ranged from 8–13 1 kg−1. No effect of dose was observed on the pharmacokinetic parameters. This suggests that the dose‐dependent effects of 7,12‐DMBA carcinogenesis are related to its transient disposition characteristics.
Immunosuppressive effect of cyclosporine in the hyperlipidemic rat model
Authors: Luke David R. 
Published: October 2006

AbstractThe immunosuppressive effects of 2·5 (n = 6) and 5 mg kg−1 day−1 (n = 7) of cyclosporine (CSA) given intravenously for 9 days to the immunized, hyperlipidemic Zucker rat model were compared with drug‐free animals (n = 6) and lean litter‐mates given 0 (n = 6), 5 (n = 6), and 10 mg kg−1 day−1 (n = 8) of CSA. Thus, based on body weights, both obese rats and lean litter‐mates received total doses of 0, 1, and 2 mg of CSA. No significant differences in percent change in baseline body weight were found; in contrast, spleen weights were markedly greater in treated animals compared with controls. Serum cholesterol, triglycerides, and lipoprotein levels of obese rats were significantly greater than values found in lean litter‐mates. CSA concentrations in whole blood, serum, and the lipoprotein fractions obtained 4h after the final dose were greater in obese rats compared with lean litter‐mates. Immunosuppressive activity, as assessed by ex vivo T‐lymphocyte proliferation assay, was equivocal between all rats given CSA, independent of dose and obesity, and significantly greater than control animals. Whereas serum CSA levels were correlated to cholesterol levels (r = 0·95, p ± 0·0001), there were no significant correlations with immunosuppressive activity. The present data suggest that increased binding of CSA to lipoproteins in the vascular compartment does not significantly impact on its immunosuppressive activity.
Nonlinear pharmacokinetics of hepatobiliary transport of rose bengal in rats after iv bolus administration with varying doses
Authors: Wang Huan Kui , Miyachi Seiji , Yamazaki Masayo , Sawada Yasufumi , Chung Youn Bok , Iga Tatsuji , Hanano Manabu , Sugiyama Yuichi 
Published: October 2006

AbstractTo investigate the nonlinear kinetics in the hepatobiliary transport of rose bengal (RB), the time profiles of plasma concentration and biliary excretion rate after its i.v. administration at various doses were measured in rats. The total body clearance decreased remarkably with increased dose. The hepatic uptake clearance also showed a similar dose dependency, and saturation of hepatic uptake at least partly accounts for the dose‐dependent change in total body clearance. The peak biliary excretion rate approached the transport maximum (approximately 150 nmol min−1 kg−1) with increased dose. To further clarify which process in RB hepatobiliary transport has nonlinearity, we analysed thus obtained data based on a three‐compartment model. The hepatic uptake and sequestration rate constants decreased remarkably with increased dose. The initial hepatic uptake rates assessed from the plasma disappearance rate during the early phase fit well to the Michaelis‐Menten equation with a saturable and a nonsaturable component. The maximum uptake velocity and Michaelis constant were 4·7 μmol min−1 kg−1 and 360 μM, respectively. That hepatic uptake has a much higher capacity (about 30 fold) than biliary excretion suggests that biliary excretion can be a rate‐determining process in the overall hepatobiliary transport of RB. We conclude that the saturation of both hepatic uptake and biliary excretion could be the main causes for the nonlinear pharmacokinetics of hepatobiliary transport of RB.