bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl
Authors: Caramella C. , Ferrari F. , Bonferoni M. C. , Sangalli M. E. , Di Valserra M. De Bernardi , Feletti F. , Galmozzi M. R. 
Published: October 2006

AbstractSix preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non‐disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus.The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and td of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and td between 149 and 291 min.The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half‐life t1/2 (7.12 h), while apparent t1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for Cmax and AUC values, and no relationships could be established with the type of formulation.An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p <0.05).In a few cases the Wagner‐Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the ‘Levy's plot’ (per cent released versus per cent absorbed) approach and provided further support for the correlation found.
Influence of food on the disposition of the monoamine oxidase‐A inhibitor brofaromine in healthy volunteers
Authors: Degen P. H. , Cardot J. M. , Czendlik C. , Dieterle W. 
Published: October 2006

AbstractThe effect of food on the bioavailability of brofaromine hydrochloride was investigated in a randomized cross‐over study. Eight healthy male volunteers were given single peroral doses of 75 mg brofaromine hydrochloride after overnight fasting or a fat‐ and proteinrich breakfast. Mean (± SD) areas under the plasma concentration‐time curves (AUC) were 9.66 (2.35) μmoll−1 h when given to the fasted volunteers and 11.82 (3.78) μmoll−1 h (p = 0.0413) when given after a substantial breakfast. Mean (± SD) maximum plasma concentrations (Cmax) were 0.71 (0.13) μmoll−1 when given to the fasted volunteers and 0.85 (0.22) μmoll−1 (p > 0.05) when given after breakfast. Thus, both the average AUC and Cmax were increased by approximately 20 per cent when brofaromine hydrochloride was given with food. The times when Cmax was reached (tmax) as well as the elimination half‐lives were not influenced by concomitant intake of food. The tolerability was the same whether brofaromine was given before or after food in healthy volunteers. The slight effect of food on the bioavailability of brofaromine should be of little therapeutic consequence because of the observed wide inter‐subject variability of the plasma levels.
Pharmacokinetics of the new antiasthma and antiallergy drug, azelastine, in pediatric and adult Beagle dogs
Authors: Adusumalli V. E. , Wichmann J. K. , Wong K. K. , Kucharczyk N. , Sofia R. D. 
Published: October 2006

AbstractThe plasma concentrations and relative bioavailability of azelastine hydrochloride (AZ) and its desmethyl metabolite (DAZ) after a single and 10 once‐a‐day oral doses of 2.5 mg kg−1 AZ were determined in adult male and female and pediatric male and female beagle dogs. The pediatric and adult dogs were 4–6 weeks and 1–2 years of age, respectively. An analysis of variance (ANOVA) was performed on the bioavailability parameters among all groups and between the first and last doses. No statistically significant (p <0.05) sex‐related differences in the bioavailability parameters were observed. The peak concentration (Cmax) of AZ, especially after the first dose, was significantly higher in pediatric dogs than that in adult dogs, whereas following the multiple AZ administrations, the bioavailability parameters for the last dose were similar in the two age groups. The apparent volume of distribution (Vss) of AZ suggested that the drug was extensively distributed into tissue in adult as well as in pediatric dogs. The Vss was considerably smaller in pediatric dogs, which may explain the higher Cmax in this age group. The bioavailability of the metabolite in adult dogs after multiple administration of AZ was higher than that in pediatric dogs. Although some differences in the parameters among the groups are statistically significant, they do not appear to have any biological significance. Therefore, similar AZ dosages may be required in pediatric and in adult populations to achieve optimum therapeutic drug levels.
Disposition of SK&F L‐190144 in rats and monkeys after oral, intravenous or ocular administration
Authors: Tang‐Liu Diane D‐S. , Richman Joseph B. , Lin Paul , Selim Sami 
Published: October 2006

AbstractThe objective of the study was to investigate the systemic disposition of 14C‐SK&F L‐190144 after single intravenous (10mg kg−1) and oral (200 mg kg−1) doses to rats and after single intravenous and ocular doses (0.33 mg kg−1) to monkeys.After the intravenous dose, the blood concentration‐time profile of 14C‐SK&F L‐190144 followed a rapid triexponential decline with half‐lives of 2.5, 15, and 246 min in rats and 3, 19, and 2520 min in monkeys. The 14C‐label in blood was mainly the parent compound. The terminal elimination half‐life detected in rats using the urinary excretion rate‐time data was 700 min. The total body clearance values were 17.6 ± 2.1 (mean ± SD, n = 6) and 1.11 ± 0.41 (n=4) mlmin−1 kg−1 for rats and monkeys, respectively. Both species had similar values of volume of distribution at the terminal phase, 4 to 6 l kg−1, and similar excretion patterns, approximately 60 per cent and 30 per cent of the dose were excreted in the urine and feces, respectively.14C‐SK&F L‐190144 was not absorbed orally in rats with the majority of the dose recovered in the feces. Following ocular administration to monkeys, the plasma drug concentrations peaked at 8 h post‐dosing but did not reach a biexponential elimination phase until 18 h post‐dosing, suggesting slow systemic absorption of drug from the ocular site. The monkeys excreted 42 per cent of the dose in urine and 50 per cent in feces after ocular administration. This increase in fecal excretion compared to the intravenous route of administration may have been due to the slow absorption by the ocular and nasal tissues altering the relative proportions of drug elimination via the renal and hepatic routes, or to a proportion of the dose passing into the gastrointestinal tract and exiting unabsorbed.Study results demonstrate similar excretion patterns and volume of distribution after intravenous administration in both species. The slow terminal elimination phase in monkeys was attributed to the low body clearance. The low oral bioavailability was possibly due to the poor partitioning behavior of the drug (logarithm of partition coefficient ‐ 2.6). A significant fraction of the dose was absorbed in the body via the ocular route.
Cocaine disposition in discrete regions of rat brain
Authors: Javaid J. I. , Davis J. M. 
Published: October 2006

AbstractIt has been proposed that various effects of psychoactive drugs on the central nervous system may be related to the capacity of the drug to selectively concentrate in specific regions of the brain. In rat brain, cocaine effects on striatal and nucleus accumbens dopaminergic systems show quantitative differences. However, the disposition of cocaine in various brain regions has not been reported. In the present studies we examined the cocaine concentrations over time in serum and discrete brain regions of the rat after single intraperitoneal (i.p.) injection. At different time points (5, 10, 20, 30, 60, 120, and 240 min) after i.p. injection of cocaine hydrochloride (10 mg kg−1, free base) the rats were decapitated and cocaine in serum and various brain regions was quantitated by a specific gas liquid chromatographic method. There was large inter‐individual variability in different rats at each time‐point. The disposition pattern of cocaine in rats after i.p. administration was similar to that observed in humans after intranasal administration. Initial absorption rate was rapid and, on average, the peak levels of cocaine were achieved in 10 min. The cocaine levels remained relatively high over the next 50 min indicating continual absorption, and then declined with a rate such that the levels 4 h after cocaine administration were undetectable in most of the animals. The overall changes in cocaine levels in various brain regions paralleled the serum concentrations. The area under the cocaine concentration‐time curve (AUC) revealed more than three‐fold differences in cocaine accumulation in various brain regions. This unequal disposition of cocaine may be responsible in part for differential biochemical effects in different brain regions.
Dual effect of valproic acid on the pharmacokinetics of phenytoin
Authors: Lai Ming‐Liang , Huang Jin‐Ding 
Published: October 2006

AbstractTo evaluate the effects of valproic acid on the disposition of phenytoin, a single dose of 600 mg valproic acid and multiple doses of valproic acid (200 mg four times a day for 5 days) were administered together with a single oral dose of 600 mg phenytoin to 12 young male volunteers. Fraction of unbound phenytoin and the area under curve (AUC) of the total and unbound phenytoin in plasma were compared with the control phase in which only 600 mg phenytoin was given. Valproic acid increased the unbound fraction of phenytoin in both single‐ and multiple‐dose studies by 15 per cent and 41 per cent, respectively. Single‐dose valproic acid increased the total AUC of phenytoin by 11 per cent. Multiple‐dose valproic acid decreased the total AUC by 7 per cent. Single‐and multiple‐dose valproic acid increased the unbound AUC by 25 per cent and 18 per cent, respectively, probably due to the inhibition on the metabolizing enzymes. We concluded that there are at least two mechanisms involved in valproic acid‐phenytoin interaction. Whereas valproic acid displacing phenytoin on the plasma protein decreased the total drug concentration of phenytoin, the enzyme inhibition by valproic acid increased both the total and unbound concentration of phenytoin. The two conflicting mechanisms may result in different effects on the total plasma concentration of phenytoin. Therapeutic drug monitoring based on the total concentration of phenytoin may be misleading when valproic acid is co‐administered.
Influence of food intake on the pharmacokinetics of a sustained release formulation of sodium valproate
Authors: Royer‐Morrot Marie‐Jose , Zhiri Azzedine , Jacob Francine , Necciari Jose , Lascombes Francoise , Royer Rene Jean 
Published: October 2006

AbstractThe effect of food intake on the pharmacokinetics of DEPAKINE® CHRONO 500 mg (Sanofi, France), a sustained release formulation containing 333 mg sodium valproate and 145 mg valproic acid, was studied in 12 young healthy female volunteers. Relative to fasting conditions (F), when the tablet was given at the midpoint of the breakfast (NF), the maximum concentration (F: 34.6 ± 8.9 μg ml−1 and NF: 40.9 ± 7.3 μg ml−1; p = 0.014) and the mean cumulative amount absorbed up to time 6 h (F: 76.3 ± 11.8% and NF: 90 ± 10.4%; p = 0.0099) were significantly increased. Nevertheless, the extent of absorption (F: 46.7 ± 9.9 mg l−1; NF: 48 ± 7.7 mg l−1) was not significantly affected. There was no change in the area under the curve (1129 μg.h ml−1), in the mean residence time (28 h), or in the elimination half‐life (16 h). On the basis of this study, the question as to whether DEPAKINE® CHRONO should be administered to subjects in the fasting or non‐fasting state would not appear to be a major consideration when deciding on the regimen.
Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to spontaneously hypertensive rats and DOCA‐salt induced hypertensive rats
Authors: Han Kye S. , Lee Sun H. , Lee Myung G. , Kim Nak D. 
Published: October 2006

AbstractThe pharmacokinetics and pharmacodynamics of bumetanide were investigated after intravenous (i.v.) administration, 10 mg kg−1, and oral administration, 20 mg kg−1, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate‐salt induced hypertensive rats (DOCA‐salt rats). After i.v. administration, the pharmacokinetic and pharmacodynamic parameters of bumetanide did not vary significantly between SHRs and the control Wistar rats. Similar results were also shown between DOCA‐salt rats and the control Sprague‐Dawley (SD) rats. After oral administration, the AUC0–12 h decreased significantly (186 versus 335 μg min ml−1) in SHRs and this resulted in decreased F(15.4 versus 23.6 and 2.78 versus 5.76% using two equations) in SHRs when compared with the control Wistar rats, although none of the other pharmacokinetic parameters varied significantly between SHRs and Wistar rats. This effect seemed to be due to the decreased enterohepatic recirculation of bumetanide in SHRs: the amounts of both bumetanide and its glucuronide product, which are capable of enterohepatic recirculation, excreted in 8 h bile juice decreased significantly in SHRs (11.3 versus 37.4 μg as expressed in terms of bumetanide) when compared with Wistar rats. The pharmacodynamic parameters did not vary significantly between SHRs and Wistar rats after oral administration of bumetanide. The pharmacokinetic and pharmacodynamic parameters of bumetanide did not vary significantly between DOCA‐salt rats and SD rats after oral administration of the drug. The liver weights compared to body weight increased significantly in SHRs when compared with Wistar rats and the corresponding values for the kidney increased significantly in DOCA‐salt rats when compared with SD rats.
Intravenous verapamil kinetics in rats: Marked arteriovenous concentration difference and comparison with humans
Authors: Manitpisitkul Prasarn , Chiou Win L. 
Published: October 2006

AbstractThe pharmacokinetics of verapamil, a calcium channel blocker, were studied in male Sprague—Dawley rats following i.v. administration at a dose of 1 mg kg−1. Both arterial and venous blood were collected and the plasma drug concentrations were determined by reversed‐phase high‐performance liquid chromatography. Verapamil was distributed to the extravascular tissues very rapidly as indicated by the large Vdss (2.99±0.57 1 kg−1) and Vdβ (5.08 ± 0.541 kg−1). The apparent terminal plasma T1/2, MRTiv, and CLp were 1.59 ± 0.46, 1.26 ± 0.12 h, and 40.4 ± 9.73 ml min−1 kg−1, respectively. Marked arterial/venous differences were found with a considerable influence on the MRT and Vdss, and the terminal phase venous levels were higher than arterial levels by 103, 69, and 90%, respectively, for the three rats studied. The distribution of verapamil between plasma and erythrocytes occurred very rapidly and was identical in vitro and in vivo. The average blood to plasma and plasma to blood cell concentration ratios were 0.85 and 1.47, respectively. In contrast to propranolol, blood data rather than plasma data should be used to predict the hepatic extraction ratio of verapamil (0.87). The plasma protein binding of verapamil in humans (90%) and rats (95%) were quite similar and constant over the wide concentration range studied. A comparison of some pharmacokinetic parameters between rats and humans is presented and the potential shortcomings of using T1/2 or CLp and the advantage of using CLu (unbound plasma clearance) in interspecies scaling is also discussed.
Pharmacokinetics of oral L‐isoidide mononitrate in rats
Authors: Tzeng Tsang‐Bin , Fung Ho‐Leung 
Published: October 2006

AbstractL‐isoidide mononitrate (L‐IIMN) is the most potent mononitrate vasodilator described so far in the literature. Since other mononitrates, such as isosorbide‐5‐mononitrate and isosorbide‐2‐mononitrate, have been shown not to be subject to first‐pass metabolism, we examined the pharmacokinetics of L‐IIMN after oral administration to determine whether this compound also exhibited this behavior. An oral dose of 2 mg kg−1 L‐IIMN dissolved in normal saline was given to seven rats. Absorption of L‐IIMN after dosing was rapid with an apparent absorption half‐life of 9.5 ± 3.6 min (mean ± SD). Plasma L‐IIMN concentrations peaked between 5 and 20 min after dosing and declined thereafter in an apparently monoexponential manner. The average elimination half‐life was 11.9±1.7 min (mean ± SD). Oral bioavailability was estimated to be about 50%. Thus, unlike the other mononitrates so far examined in the literature, L‐IIMN exhibits incomplete bioavailability. This pharmacokinetic behavior, however, is consistent with its faster systemic clearance compared to other organic mononitrates.
Kinetic analysis of tissue distribution of doxorubicin incorporated in liposomes in rats (II)
Authors: Harashima Hideyoshi , Midori Yukari , Ohshima Shunji , Yachi Kiyoto , Kikuchi Hiroshi , Kiwada Hiroshi 
Published: October 2006

AbstractThe objective of this study is to perform kinetic modelling of the tissue distribution of doxorubicin encapsulated into liposomes (L‐DXR), especially to the heart and liver. The release process of doxorubicin (DXR) from liposomes in blood was quantified by a release clearance. This parameter defines a release rate of DXR based on the concentration of L‐DXR in blood and was estimated from kinetic modelling of DXR distribution to the heart after L‐DXR administration. The distribution of free DXR to the heart was modelled separately. The experimental data for this modelling were reported previously (Harashima et al., Biopharm. Drug. Disposit., 13, 155–170 (1992)). This analysis provided a free DXR concentration profile as well as a release clearance of DXR after L‐DXR administration. There was a remarkable difference in the free DXR concentration in blood between free and liposomal administration. The area under the DXR curve in the heart was reduced by approximately one third from that for the first two hours after DXR administration by liposomal encapsulation, which could be the reason for reduced cardiac toxicity. In our previous report, the distribution of L‐DXR to the liver was shown to be explained by a sequentially linked two‐compartment model with efflux process. The validity of this efflux model was examined in this study by a repeated dose study. The apparent uptake clearance decreased with time and showed a second peak after the repeated dose, which justified the efflux model. These kinetic analyses give quantitative understanding of the effect of liposomal encapsulation on the tissue distribution of DXR.
Influence of albumin on isoprenaline and propranolol effects on isolated rat uterus
Authors: Morgan Denis J. , Richmond Barbara H. , Malta Errol 
Published: October 2006

AbstractWe investigated the effect of albumin (6%) on the (±)‐isoprenaline‐induced relaxation of strips of isolated rat uterus and its antagonism by (−)‐propranoioi. The mean isoprenaline EC50 in the presence of albumin was significantly less than that in the absence of albumin (geometric mean 1.94 ± 3.33 versus 3.21 ± 3.50 nM, respectively; n = 14; p = 0.006, paired t test). This indicates enhancement of isoprenaline activity by albumin which could not be explained by protein binding, as this would have reduced activity. Geometric mean control KB values for inhibition of isoprenaline by propranolol at 26.8 and 500 nM were 0.835 ± 1.68(n = 10) and 0.889 ± 1.60 nM (n = 34), respectively. In the presence of 6% albumin, KB for propranolol was increased significantly to 13.3 ± 1.8 nM (n = 27, p <0.001). Calculation of KB in terms of the measured propranolol unbound concentration of 26.8 nM, after taking into account the lower isoprenaline EC50 in the presence of albumin, yielded a mean value of 0.725 ± 1.86 nM, which was not significantly different from either control (p >0.05). Therefore, propranolol activity was as predicted by the unbound drug concentration in Contrast to isoprenaline activity. We conclude that albumin can alter in vitro drug activity by mechanisms in addition to the reduction of unbound drug concentration.
An estimate of the rate of direct drug diffusion from the surface of heart and kidney—implications for their representation as compartments
Authors: Huang Yi Fei , Upton Richard N. 
Published: October 2006

AbstractIn many regional pharmacokinetic experiments and models, the anatomical boundaries of the heart and kidney are intrinsically assumed to be barriers for drug diffusion such that these organs can be represented as one or more compartments. To test this, an experimental preparation was developed in which the heart and kidney of anaesthetized sheep were surrounded with 0.9% saline. The rate of drug diffusion from the surface of the organs into the saline was examined during constant‐rate i.v. drug infusions. It was found that the maximum clearances of lidocaine and procainamide into the pericardial saline were 10.3–11.6 and 0.6–2.1 ml min−1 respectively, and the values for the kidney were 0.3–0.6, 0.1–1.0 and 0.4–1.3 ml min−1, for lidocaine, procainamide, and meperidine respectively. These corresponded to calculated times of 4–481 min to reach the steady‐state saline concentration depending on the drug and the organ. The steadystate ratio of the saline concentrations over the arterial blood drug concentrations usually ranged from 0.5–1.0. It is concluded that drugs can rapidly enter regions of low or no perfusion surrounding these organs, and that the concept of treating the heart and kidney as compartments may not be valid in certain ‘worst‐case’ situations.
The structural barrier of absorptive mucosae: Site difference of the permeability of fluorescein isothiocyanate‐labelled dextran in rabbits
Authors: Hosoya Ken‐Ichi , Kubo Hiroyuki , Natsume Hideshi , Sugibayashi Kenji , Morimoto Yasunori , Yamashita Shinji 
Published: October 2006

AbstractThe permeability of fluorescein isothiocyanate‐labelled dextran (FD, M.W. 4400‐71 200) across nasal, buccal, duodenal, jejunal, ileal, colonic, and rectal mucosae excised from rabbits has been measured to estimate the structural barrier of absorptive mucosae using Ussing‐type diffusion chambers. The permeability coefficient of FD in all these mucosae decreased with increasing molecular weight. The rank order of FD permeability did not always correlate with the electrical resistance of the mucosae. Among components of the small intestine (duodenum, jejunum, ileum) and the large intestine (colon, rectum), however, the rank order of FD permeability corresponded to the magnitude of the electrical resistance in each instance; the upper colonic mucosa showed the highest permeability, especially in FD of low molecular weight, and permeability of the rectal mucosa was lowest except for the duodenal mucosa. The nasal mucosa showed the lowest electrical resistance and the highest permeability of those studied, suggesting that it has a leaky structural barrier.