bluuebunny/crossref_metadata_2025_split huggingface dataset:
First‐pass metabolism of acetaminophen in rats after low and high doses
Authors: Hirate Junji , Zhu Chun‐Yan , Horikoshi Isamu , Bhargava Vijay O. 
Published: October 2006

AbstractThe first‐pass metabolism of acetaminophen was examined in rats after the administration of 15, 30, 150, and 300 mg kg−1 doses by intra‐arterial, intravenous, portal vein, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5 h after drug administration. The first‐pass effect after oral administration (oral extraction) was extensive (Eo = 0·34–0·50) at all doses administered. Calculation of the relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction of acetaminophen indicated that the major contribution was due to the gastrointestinal tract at all doses studied (Eg = 0·33–0·50). At higher doses (150 and 300 mg kg−1) clearance was lower possibly due to the saturation of acetaminophen sulfate formation. However, even at these high doses, the contribution of the gastrointestinal mucosa to the oral extraction remained unchanged. Therefore, it appears that the apparent dose‐dependent characteristics of acetaminophen metabolism may be due to the saturation of acetaminophen sulfate formation in the liver.
Pharmacokinetics and absolute bioavailability of ibuprofen after oral administration of ibuprofen lysine in man
Authors: Martin W. , Koselowske G. , Töberich H. , Kerkmann Th. , Mangold B. , Augustin J. 
Published: October 2006

AbstractThe lysine salt of d, l‐2‐(4‐isobutylphenyl)‐propionic acid (ibuprofen lysine) was administered as a single oral dose of 500 mg by means of commercially available coated tablets (Imbun®). To assess the absolute bioavailability of ibuprofen after its oral application as a lysine salt, intravenous injections of ibuprofen solutions containing 200 mg and 400 mg of the drug served as reference application. In a partially randomized cross‐over design, 8 healthy male volunteers received three different single dose administrations which were separated by wash‐out periods of 4 days each. Ibuprofen plasma concentrations were determined by HPLC using direct injection, pre‐column enrichment and column switching techniques. From the results of intravenous injections one can deduce linear ibuprofen pharmacokinetics within the considered dosage range, with corresponding AUC0−∞ values of 3786 μg min ml−1 and 7260 μg min ml−1 for the 200 mg and 400 mg doses, respectively. The values of plasma clearances as well as those of different volumes of distribution showed remarkable constancy after evaluation from both intravenous injections. The absorption of orally administered ibuprofen lysine proved to be rapid, resulting in a mean peak plasma level (Cmax) of 31 μg ml− ibuprofen and in a mean time to peak (tmax) of 45 min. The absolute bioavailability of ibuprofen amounts to 102·7 percent, indicating a complete absorption of ibuprofen when administered as its lysine salt. Drug tolerability was excellent for the oral administration of ibuprofen lysine as well as for the intravenous treatments with ibuprofen free acid. Only mild and transient adverse drug reactions such as mild burning or dragging sensation during injection or mild redness at the site of injection were reported.
Effects of cefotaxime on the serum protein binding of sulfisoxazole
Authors: Souich P. Du , Calvo R. , Erill S. 
Published: October 2006

AbstractThe possible acylating effects of cefotaxime on sulfisoxazole binding to serum proteins were evaluated in vitro in samples of human sera incubated with 50–1000 μ ml−1 cefotaxime at 37° for 1 h and then dialyzed against saline. This incubation resulted in concentration‐related increases in the free fraction of sulfisoxazole (+25 per cent, +30 per cent, and +45 per cent, with 250, 500, and 1000 μ ml−1 cefotaxime, respectively). Sulfisoxazole binding was also studied in samples of sera from patients given prophylactic cefotaxime (3 gd−1, IV) following elective surgery. Sulfisoxazole free fraction increased from 7·6 ± 0·7 per cent in samples obtained before starting treatment to 9·2 ± 0·8 per cent 24 h thereafter, and to 10·4 ± 1·0 per cent after 5 days of treatment, but this difference was not statistically significant. A Scatchard plot of pooled samples showed a reduction in overall affinity (from 2·38 × 10−4M to 1·77 × 10−4) without changes in the number of binding sites. The effects of cefotaxime on sulfisoxazole binding and kinetics were also studied experimentally in the rabbit. Treatment with 30 mg kg−1 cefotaxime t.i.d. for 2 days increased the unbound fraction of sulfisoxazole in vivo, from 17·2 ± 2·9 per cent to 27·3 ± 3·6 per cent (p < 0·02). Treatment with high doses of cefotaxime, and perhaps other 3‐acetoxymethylcephalosporins, may result in changes in the serum protein binding of some acidic drugs.
Activation of beclomethasone dipropionate by hydrolysis to beclomethasone‐17‐monopropionate
Authors: Würthwein Gudrun , Rohdewald Peter 
Published: October 2006

AbstractThe relative affinity of beclomethasone (B), beclomethasone‐17‐monopropionate (17‐BMP), beclomethasone‐21‐monopropionate (21‐BMP), and beclomethasone dipropionate (BDP) has been determined. BDP binds to the glucocorticoid receptor with about half the affinity of the potent glucocorticoid dexamethasone (Dexa), B was found to be 0·75 times less active than Dexa. The 21‐BMP has no binding affinity whereas the 17‐BMP is about 13 times as potent as Dexa. The affinity data indicate that metabolism of BDP to 17‐BMP is an important activation step. To evaluate the relationship between local and systemic activity incubation studies with BDP in human lung, simulated gastric and intestinal fluid and plasma were performed. In cytosol from human lung cells BDP is hydrolysed rapidly to the more stable 17‐BMP. During gastric passage BDP is stable but is immediately hydrolysed to 17‐BMP in intestinal fluid. In human plasma BDP is hydrolyzed to 17‐BMP and an interesterification of 17‐BMP to the inactive 21‐BMP was also found.
Bioavailability and cardiovascular safety of dexatrim® (phenylpropanolamine hydrochloride) from a controlledrelease caplet
Authors: Shargel Leon , Silverman Harold I. , Cohen Peri , Brisson Jerry , Dennis Susana 
Published: October 2006

AbstractThe bioavailability and pharmacokinetics of phenylpropanolamine hydrochloride (PPA HCl) from a Dexatrim® controlled‐release (CR) caplet and solution was studied. Each subject (n = 12) received either a 75 mg PPA HCl CR caplet once daily or a 25 mg PPA HCl solution given three times a day. All subjects received the medication for 4 consecutive days. On Day 1, the mean ± SEM, AUC, tmax, and Cmax values were 1651 ± 127 ng x h ml−1, 4·5 ± 0·26 h and 143 ± 13·5 ng ml−1, respectively, for the CR caplet and 1716 ± 90·3ng × h ml−1, 1·25 ± 0·08 h and 126 ± 5·8 ng ml−1 for the solution, respectively. At steady state (Day 4), the mean ± SEM, AUC, tmax, and Cmax values were 1832 ± 101 ng x h ml−1, 4·17 ± 0·17 h and 151 ± 6·5 ng ml−1, respectively, for the CR caplet and 2014 ± 116 ng x h ml−1, 1·33 ± 0·09 h and 143 ± 8·7 ng ml−1, respectively, for the solution. The data from Day 1 were fitted to an oral one compartment model with a first order absorption rate constant, kA, first order elimination rate constant, k and lag time. The mean ± SEM, kA, elimination half‐life and lag time for PPA HCl from the CR caplet were 0·488 ± 0·182 ng h ml−1, 5·84 ± 1·66 h and 0·394 ± 0·224 h, respectively. The mean ± SEM, kA, elimination half‐life and lag time for PPA HCl from the solution were 2·87 ± 1·51 ng x h ml−1, 3·73 ± 1·21 h, and 0·325 ± 0·101 h. respectively. The smaller apparent kA and longer elimination half‐life for PPA HCl from the CR caplet is due to the slow release of PPA HCl, thereby slowing its absorption producing sustained plasma drug concentrations. Blood pressures (supine and sitting) and heart rates measured at the time of blood sampling after the administration of the PPA HCl dosage forms demonstrated no clinically significant relationship between cardiovascular response and PPA HCl plasma concentration. These data demonstrate the bioavailability and pharmacokinetics of PPA HCl from a CR caplet and an immediate release solution.
Pharmacokinetics of pafenolol in the rat: A suitable model for studying absorption mechanisms of a drug exhibiting unusual absorption properties in man
Authors: Lenneras Hans , Regårdh Carl G. 
Published: October 2006

AbstractThe pharmacokinetics of pafenolol, a highly selective β1‐adrenoceptor antagonist, have been studied in starved and unstarved rats. Separate groups received intravenous doses (0·3 and 3·0 μmol kg−1) and oral doses (1 and 25 μmol kg−1). The systemic clearance of pafenolol was constant in the dose range investigated where the absolute oral bioavailability increased from 15 to 27 per cent in the starved and from 9·1 to 21 per cent in the unstarved rats, when the oral dose was raised from 1 to 25 μmol kg−1. The blood concentration profile after an oral solution of pafenolol exhibited two peaks in the majority of the rats. The major part of the absorption was associated with the second peak which appeared about 4 h after dosing in both starved and unstarved rats. Food lowered the degree of bioavailability and shifted the t, to about 1 hour compared to half an hour in starved rats. The low bioavailability was primarily due to incomplete uptake from the gastrointestinal tract. Our study shows that pafenolol is absorbed in a similar way to that in man. The mechanisms behind the dose‐dependent bioavailability and the two peaks in the absorption profile after an oral solution will be further explained in the rat.
Regional pharmacokinetics II. Experimental methods
Authors: Upton Richard N. , Runciman William B. , Mather Laurence E. 
Published: October 2006

AbstractRegional pharmacokinetics is the study of the drug concentrations in specific regions of the body. It allows greater insight into the mechanisms of drug disposition than the study of systemic blood concentrations. Experimental methods in regional pharmacokinetics and their applications and limitations are reviewed. Post‐mortem tissue biopsies give the drug concentrations in highly specific regions of the body, but require a large number of animals. Serial tissue biopsies yield the time‐course of drug concentrations in individual animals, but have limited applications. Regional blood sampling in vivo requires catheterization of blood vessels and a measure of regional blood flow, but allows repeated measurements of the time‐course of regional drug concentrations in an individual. In contrast, artificially perfused regions allow greater control of perfusate flow and composition, but are less representative of the in vivo situation. These factors can be retained in some animals by surgically transplanting organs to another location to increase access. Tissues slices and cell cultures can examine drug uptake in the absence of perfusion, and tissue homogenates can be used to study the in vitro rates of drug metabolism and tissue drug binding.
Central nervous system uptake kinetics of pentylenetetrazol in the developing rat
Authors: Haberer Lynda J. , Pollack Gary M. 
Published: October 2006

AbstractThe present investigation was undertaken to examine the brain uptake kinetics of the central nervous system (CNS) stimulant pentylenetetrazol (PTZ) during postnatal development. This study represents part of an ongoing effort to develop an appropriate seizure model for investigations of anticonvulsant action in the developing rat. The systemic pharmacokinetics of PTZ were examined in male and female adult animals following both intravenous (IV) and subcutaneous (SC) injection. PTZ administered SC was absorbed rapidly and was completely bioavailable in both genders. No statistically significant gender‐dependent differences in the disposition of PTZ were identified. To examine the CNS uptake kinetics of PTZ, animals of four different age groups (5, 10, 20, and 60 days postnatal) received timed SC infusions of PTZ. Significant age‐related differences in the rate of uptake of PTZ into the CNS were observed. These differences paralleled the previously reported age‐dependent changes in the dose of PTZ required to elicit seizure activity. The results of this investigation indicate that the apparent age‐related change in sensitivity to the convulsant effects of PTZ is due in part to age‐dependent uptake of the convulsant into brain tissue.
Age‐dependent changes in first‐pass metabolism of acetaminophen in rats
Authors: Hirate Junji , Zhu Chunyan , Horikoshi Isamu , Bhargava Vijay O. 
Published: October 2006

AbstractThe contribution of gastrointestinal tract (GIT), liver, and lung towards the first‐pass metabolism of acetaminophen was examined using 3‐week‐old, 10‐week‐old and 1‐year‐old rats after administration of 30mgkg−1 doses by intra‐arterial, intravenous, intraperitoneal, and oral routes. Plasma concentrations of acetaminophen and its two major metabolities, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5h after drug administration. Total oral extraction of acetaminophen was extensive in 10‐week‐old and 1‐year‐old rats (Eo = 0·46) and the major contribution to the overall first‐pass metabolism was due to the GIT (Eg = 0·50–0·53). Oral extraction in 3‐week‐old rats was minimal (Eo = 0·10) and there did not appear to be an extraction by the GIT (Eg = 0·00). These results suggest that the ability of GIT to metabolize acetaminophen to glucuronide and sulfate is undeveloped in the infant rats. No changes in the contribution of different organs to the first‐pass metabolism of acetaminophen was observed 10 weeks after birth. Pharmacokinetic parameters for acetaminophen in infant rats (3‐week‐old) and 10‐week‐old rats were similar after drug administration by the intra‐arterial and intravenous routes.
Pharmacokinetics of stobadin and of the sum of its metabolites in rats during repeated administration
Authors: Kállay Zoltán , Šoltés Ladislav , Trnovec Tomáš 
Published: October 2006

AbstractStobadin dihydrochloride was administered p.o. to rats at a dose of 1 mg kg−1 once daily for 25 consecutive days. The peak and trough concentrations of the sum of stobadin metabolites, determined from Days 6–16 of treatment, demonstrated a steady‐state. The mean daily excretion of 3H‐radioactivity during this period was 43 per cent and 52 per cent of the administered dose into urine and faeces, respectively. The terminal half‐life of stobadin in plasma following a 25‐day chronic treatment was 78·3 min, which was shorter than the value of 95·3 min, determined in a single dose experiment. The data indicate that no accumulation of stobadin and of its labelled metabolites occurs in the course of repeated administration of 3H‐stobadin.
Endogenous plasma N‐acetylcysteine and single dose oral bioavailability from two different formulations as determined by a new analytical method
Authors: Gabard Bernard , Mascher Hermann 
Published: October 2006

AbstractA method to quantitate N‐acetylcysteine in plasma using reductive cleavage with tributyl‐phosphine and post‐HPLC column derivatisation with o‐phthalaldehyde is described. Using this method, endogenous average concentrations of 0·08 μM were measured in 10 volunteers participating in a crossover study to compare the bioavailability of two different formulations of N‐acetylcysteine. The drug was detected in plasma for up to 12h after administration of a single oral dose (200 mg); the Cmax values were up to 20 times the endogenous levels. The sensitivity and selectivity of the method should thus enable the behaviour of N‐acetylcysteine after oral administration to be properly described and bioavailability studies to be performed.
Disposition and pharmacodynamics of dichloroacetate (DCA) and oxalate following oral DCA doses
Authors: Curry Stephen H. , Lorenz Anthea , Pei‐ichu  , Limacher Marion , Stacpoole Peter W. 
Published: October 2006

AbstractHealthy volunteers received intravenous and/or oral doses of sodium dichloroacetate (DCA) in various single and multiple dose regimens. A crossover bioavailability study proved abortive because second and subsequent doses showed significantly longer terminal elimination half‐lives (means 3·64 h and 9·9 h, respectively) than was the case for initial doses (1·58 h). A parallel bioavailability comparison failed to show that oral doses were significantly different from 100 per cent bioavailability (AUCoral, 604μgh−1 ml−1; AUCi.v., 489μgh−1 ml−1). The time required to elapse between individual doses, in order to prevent second doses having relatively long half‐life values, varied in different individuals from 1 week to greater than 3 months. No cardiac or central nervous system effects were recorded by echocardiography and digit symbol substitution tests, respectively. The mean renal clearance of DCA was 42·9 ml h−1. No differences were observed in DCA kinetics between male and female subjects.
Bioavailability of diltiazem as a function of the administered dose
Authors: Bianchetti G. , Regazzi M. , Rondanelli R. , Ascalone V. , Morselli P. L. 
Published: October 2006

AbstractDiltiazem undergoes extensive first‐pass metabolism; extrapolation from single to repeated administration thus underestimates plasma concentration values. In order to validate the hypothesis of a partially saturable first‐pass effect, four single doses of diltiazem (10, 20, 40, and 120 mg) were administered at weekly intervals to eight healthy volunteers. Results showed that: (a) the inter‐subject variability was highest at the lowest dose and lowest at the highest dose; (b) bioavailability was almost nil in 3 of 8 of the subjects after the administration of the 10 mg dose; (c) the mean bioavailability increased with the dose from 11·8 ± 2·5 per cent after 10 mg to 28·2 per cent after 120 mg; (d) the elimination half‐life was dose‐related; (e) the renal excretion of diltiazem increased with the administered dose from 1.0 ± 0·3 per cent after 10 mg to 3·0 ± 0·5 per cent after 120 mg; (f) the greatest amounts of circulating metabolites were present after the lowest doses. These results are consistent with a partially saturable first‐pass effect for diltiazem.
Ocular pharmacokinetics of calcium, chloride and sulphate ions after instillation in the rabbit
Authors: Hariton C. , Mandel P. 
Published: October 2006

AbstractThe ionic environment of the eye is involved in major biochemical processes which are essential for preserving the integrity of cornea and lens. The purpose of the present study was to determine the intra‐ocular penetration and the pharmacokinetic parameters of calcium, chloride and sulphate ions in the cornea, iris‐ciliary body (ICB) and lens, after administration by instillation in the rabbit eye. In order to extrapolate our results to the processes occurring in man, we followed a precise instillation protocol using a low volume (5 μl) of 45Calcium, 36Chloride and 35Sulphate, which is less than the lacrimal volume determined during the palpebral closing and performing manual blinking at a frequency of 2 min−1The results indicate an immediate trans‐corneal permeability and a rapid ocular distribution of these ions. We observe that, relative to dose, an important percentage of calcium (67·20 per cent) was entrapped in the cornea; this parameter was less important for chloride (10·19 per cent) and for sulphate ions (3·25 per cent). These values are in agreement with those predicted theoretically for trans‐corneal penetration by such compounds. On the other hand, the total degrees of penetration by chloride and sulphate ions in ICB (1·40 per cent and 0·90 per cent, respectively) and lens (0·35 per cent and 0·41 per cent, respectively) are quite similar. Calcium retention is much higher in these tissues (25·39 per cent in ICB and 16·03 per cent in lens). It seems likely that the higher degree of lens entrapment of calcium may be explained by the trans‐capsular electrical potential difference and the negative charge inside the lens and the presence of proteins possessing high affinity and binding capacity for calcium.
Diclofenac, paracetamol, and vidarabine removal during plasma exchange in polyarteritis nodosa patients
Authors: Fauvelle F. , Nicolas P. , Leon A. , Tod M. , Perret G. , Petitjean O. , Guillevin L. 
Published: October 2006

AbstractSince plasma exchange (PE) represents a major treatment for patients suffering from systemic diseases, its influence on the kinetics of three drugs was investigated: vidarabine, used in patients with polyarteritis nodosa associated with hepatitis B virus (eight subjects), and diclofenac and paracetamol for investigative purposes (five subjects). This study confirmed that vidarabine is so rapidly deaminated to form hypoxanthine arabinoside (Hx‐Ara) that no detectable concentrations were measured. Hx‐Ara levels were used to evaluate vidarabine kinetics; 19·5 ± 14·6 mg of Hx‐Ara were removed by one PE during the first week of treatment (15 mg kg−1 d−1, continuous infusion) and 7·8 ± 10·2 mg were eliminated by one PE during the second week of treatment (7·5 mg kg−1 d−1, continuous infusion). Based on the vidarabine intake per hour and the resulting quantity of Hx‐Ara removed per hour, PE recovery was quite important (ca. 30 per cent), during both the first and second weeks of continuous infusion. Data were subject to large interindividual variability. However, these results do not favor vidarabine dosage supplementation in this indication because the duration of PE is less than 8 per cent of a daily administration period. For paracetamol (1 g, single oral dose) and diclofenac (100 mg, single oral dose), the fractions of drug removed during PE effected within 2 h of drug intake, were respectively 5·0 ± 3·1 per cent and 13·6 ± 9·5 per cent, while plasmapheretic clearance reached, respectively, 13·0 ± 10·7 per cent of the systemic clearance for paracetamol and 23·0 ± 1·0 per cent for diclofenac.
Effect of co‐administration of intralipidTM on the pharmacokinetics of cyclosporine in the rabbit
Authors: Shah Ajit K. , Sawchuk Ronald J. 
Published: October 2006

AbstractThe effect of IntralipidTM co‐administration on the pharmacokinetics of cyclosporine (CyA) was studied in NZW rabbits. A single intravenous bolus dose of CyA (10 mg kg−1) mixed with 3 ml of Intralipid was administered to rabbits (n = 4). Control animals (n = 4) received the same dose of CyA without Intralipid. Serial blood samples were collected up to 12 h after the administration of CyA. Concentrations of CyA in plasma were analyzed using a HPLC method. The terminal elimination half‐life (t1/2) of CyA was significantly lower with Intralipid administration (191·25 min) than control (298 ± 59 min). The total body clearance (C1TOT) and volume of distribution (Vdss) of CyA was reduced by approximately 65–70 per cent with Intralipid administration compared to control. The free fraction of CyA in plasma with and without Intralipid administration was estimated to be 0·05 ± 0·01 and 0·17 ± 0·06, respectively. Co‐administration of Intralipid with CyA decreased both the ClTOT and Vdss resulting in a rapid elimination, i.e., decrease in a t1/2 of CyA from the body.