bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of population and standard two‐stage pharmacokinetic analyses of vigabatrin data
Authors: Yu Dale K. , Hutcheson Sam J. , Wei Greg , Bhargava Vijay O. , Weir Scott J. 
Published: October 2006

AbstractVigabatrin (VGB), an irreversible inhibitor of GABA, is being developed as an add‐on therapy for uncontrolled complex partial seizure. A single‐dose study was conducted in three groups of subjects with normal, mild‐to‐moderate, and moderate‐to‐severe renal impairment to examine the effect of renal function on the pharmacokinetics of VGB. Serial blood samples were collected up to 60 h following a single 750 mg oral dose of VGB for the quantitation of drug concentrations. The plasma VGB concentration—time data were analyzed by mixed‐effects modeling to estimate population pharmacokinetic parameters and to identify any significant demographic covariates. The parameters of VGB were also calculated by standard two‐stage techniques and then compared to the results obtained using the mixed‐effects analysis. Population VGB plasma concentration—time profiles were best described by a two‐compartment model with zero‐order absorption. Creatinine clearance was observed to significantly affect the oral clearance of VGB (p < 0.05), i.e. a linear increasing relationship existed between the two variables. Other demographic factors had no influence on VGB pharmacokinetics. There were agreements in the oral clearance, apparent volume of distribution during elimination, and half‐life estimates calculated by both methods. In addition, the conventional technique identified a linear relationship between oral and creatinine clearances. In summary, mixed‐effects modeling of serial vigabatrin data validated results determined by the standard two‐stage technique.
The penetration of amphotericin B from an Intralipid® formulation into fibrin loci in a rabbit model of candidiasis
Authors: Bouley M. , Tod M. , Chavanet P. , Petitjean O. 
Published: October 2006

AbstractThe kinetics of amphotericin B (AMB) concentrations in plasma and interstitial fluid were studied in an experimental model of Candida albicans infection in rabbits. Rabbits were infected by subcutaneously implanted fibrin clots containing the yeast. Three groups of five rabbits received a 4 mg kg−1 AMB infusion. AMB (Fungizone®) was dissolved in 5% glucose (group I) or in 20% Intralipid® at a final concentration of 1.5 (group II) or 3 mg mL−1 (group III). AMB was measured by liquid chromatography in plasma and in trypsin‐dissolved fibrin clots up to 72 h after the infusion. No significant differences in AMB plasma and interstitial‐fluid concentration kinetics between the three modes of administration were found. AMB penetration into fibrin clots was slow, with no significant differences between treatments. Thus, formulation of AMB in Intralipid does not modify either the drug's interstitial or plasma kinetics at equivalent doses.
Variability in absorption lag time of pyridoxal phosphate under fasting and pre‐ and post‐meal conditions
Authors: Takahashi Harumi , Ogata Hiroyasu , Nagai Naomi , Sugito Keiko , Shimamura Hideo 
Published: October 2006

AbstractInter‐individual variations in the absorption lag time of pyridoxal phosphate were determined after administration of an enteric‐coated tablet (EC) or a plain capsule (PC) to 113 healthy volunteers under fasting, pre‐meal, and post‐meal conditions. The absorption lag time of pyridoxal phosphate was assessed from the urinary excretion of 4‐pyridoxic acid after administration of EC and PC. Significantly larger lag times after administration of both formulations were observed under post‐meal conditions than under pre‐meal conditions (0.477 ± 0.315 h versus 0.081 ± 0.086 h for PC and 1.995 ± 1.345 h versus 1.064 ± 1.327 h for EC), indicating that the mean gastric emptying rates of both a solution and a tablet were delayed after food intake. The lag time for PC showed little inter‐individual variation with (0–1.2 h) or without food (0–0. 25 h), whereas that for EC showed markedly large inter‐individual variation, from 0.25 to 2.63 h (median, 1.5 h) in the fasting condition, from 0.25 to > 5.5 h (median 0.25 h) under pre‐meal conditions, and from 0.25 to > 5.5 h (median 1.25 h) under post‐meal conditions. The effect of food on the gastric emptying rate of a solution appears to be almost uniform, whereas that for a tablet is so unpredictable that a reliable absorption rate for an enteric‐coated tablet cannot be expected, particularly under pre‐ and post‐meal conditions.
A pharmacokinetic evaluation of HIV protease inhibitors, cyclic ureas, in rats and dogs
Authors: Wong Y. Nancy , Burcham Deborah L. , Saxton Philip L. , Erickson‐Viitanen Susan , Grubb Mary F. , Quon Check Y. , Huang Shiew‐Mei 
Published: October 2006

AbstractThe pharmacokinetics of a series of novel cyclic, non‐peptide inhibitors of HIV protease were studied in rats or dogs after intravenous and oral administration. Six symmetrically substituted cyclic urea compounds (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively inhibited HIV virus replication, with IC90, values of 0.03–1.0 μM (0.017–0.76 μg mL−1), were evaluated. Plasma concentrations were measured in rats and dogs using specific and sensitive HPLC methods. In rats, the maximum plasma concentrations of 0.21–1.88 μg mL−1 were detected within 1 h of oral administration of 10 mg kg−1 of the compounds. The elimination half‐lives ranged from 1.25 to 3.3 h in rats and the absolute oral bioavailability ranged from 18 to 100%. In dogs, the maximum plasma concentration and absolute oral bioavailability were 4.37 μg mL−1 and 48%, 1.07 μg mL−1 and 16%, and 1.48 mg mL−1 and 38% for XK234, XM311, and XM323, respectively. The data demonstrated that the maximum plasma concentrations of these cyclic ureas were several times higher than the IC90 for inhibition of viral replication after single doses of 10 mg kg−1 in rats and dogs. With this combination of high potency against virus replication and good oral bioavailability, these cyclic ureas represent a new class of compounds that are suitable for development as therapeutic agents for the treatment of HIV‐associated diseases.
The effect of different routes of administration on the metabolism of morphine: The disposition of morphine and its metabolites after topical application
Authors: Matsuzawa Takayasu , Wada Yoshio , Shimoyama Masaru , Nakajima Kae , Seki Toshinobu , Sugibayashi Kenji , Morimoto Yasunori 
Published: October 2006

AbstractThe disposition of morphine (MOR) and its metabolites in the rabbit was measured after topical administration of its hydrochloride salt (MOR · HCl), and their time course was compared with those after intravenous and oral administration. The area under the plasma concentration—time curve (AUC) ratio of metabolites/MOR after the topical application of MOR · HCl was similar to that after intravenous injection, but differed from that after oral administration. Pharmacokinetic parameters of the disposition of MOR and its metabolites were obtained by a general curve fitting of the time course of plasma concentrations of these compounds after intravenous injection of MOR · HCl and its metabolites, respectively. On the other hand, the time courses of plasma concentrations of the metabolites after intravenous, oral, and topical administration of MOR · HCl were simulated using a simple compartment model without consideration of enterohepatic circulation and the pharmacokinetic parameters obtained as above. The resulting curves of the metabolites agreed well with the observed values except for those after oral administration.These results suggest that no first‐pass metabolism of MOR · HCl occurs after percutaneous administration, and that topical administration of this salt is more advantageous than oral administration in terms of bioavailability.
Effect of ‘unstirred’ water layer in the intestine on the rate and extent of absorption after oral administration
Authors: Chiou Win L. 
Published: October 2006

AbstractThe presence of an aqueous diffusion layer or ‘unstirred’ water layer adjacent to the intestinal membrane has long been regarded as a potential barrier for intestinal absorption of compounds. Theoretical analyzes were performed in the present study to quantitatively determine the effect of this layer on the rate and extent of absorption of passively absorbed compounds with different membrane absorption half‐lives (10 to 300 min) in humans, dogs, rabbits, rats and mice. Diffusion half‐lives across this (40 μm thick) layer were estimated to be 5.8, 2.5, 1.1, 0.65 and 0.32 min, respectively, in the distended intestine of the above five species. These half‐lives are reduced by about 5‐fold when the intestine is about 80% ‘flat’ in fasting state. The results of extensive analysis indicate that the presence of such a layer is generally expected to have a relatively mild or insignificant effect on the rate of absorption and an insignificant effect on the extent of absorption. The study also indicates that an aqueous layer of 708 μm has practically no effect on the extent of absorption of progesterone, a highly lipophilic compound, in rats. For prediction of or correlation with the fraction of oral dose absorbed after oral administration, the present study indicates that use of apparent or effective permeability rather than unbiased or true wall (membrane) permeability, as advocated earlier by others, should generally suffice.
Comparative pharmacokinetics of oxaliplatin (L‐OHP) and carboplatin (CBDCA) in mice with reference to circadian dosing time
Authors: Boughattas Naceur A. , Hecquet Bernard , Fournier Charles , Bruguerolle Bernard , Trabelsi Hassen , Bouzouita Kamel , Omrane Belhadj , Lévi Francis 
Published: October 2006

AbstractCarboplatin (CBDCA) and oxaliplatin (I‐OHP) are non‐nephrotoxic platinum (Pt) compounds, which exert their main respective toxicities on the bone marrow and on the intestinal mucosa in mice. Plasma and red blood cell (RBC) drug dispositions were investigated in 324 male B6D2F1 mice after a single IV injection of CBDCA (72 mg kg−1) or I‐OHP (17 mg kg−1). Since the toxicities of either drug largely depended upon circadian dosing time, such a pharmacokinetic study was performed following injection of either Pt complex at a time of low (16 h after light onset—HALO), intermediate (0 HALO) or high (8 HALO) toxicity.Pt concentrations in plasma ultrafiltrate (PUF) and in total plasma declined in parallel and became barely detectable by 2 h following CBDCA injection. Conversely, free Pt became undetectable 1 h after I‐OHP injection, whereas sustained levels of total Pt were found 24 h post dosing. This suggested that I‐OHP had a high binding affinity for plasma proteins. Mean values of t1/2α and mean residence time (MRT) of free Pt for I‐OHP (6.7 min and 9.7 min respectively) were half those of CBDCA (12.5 min and 18.1 min respectively). The two drugs had a similar initial volume of distribution (Vdi) of free Pt (10.5 mL) in mice. However, plasma clearance of I‐OHP was twice as high (1.06 mL min−1) as that of CBDCA (0.58 mL min−1). Free Pt AUCs were eight to ten times lower for I‐OHP than for CBDCA. In contrast, erythrocyte Pt AUCs were three to four times as high for I‐OHP as for CBDCA. Circadian changes in pharmacokinetic parameters were large, yet limited to the initial distribution phase (C0, t1/2α, Vdi) as well as mean residence time. The smallest Vdi and the fastest plasma elimination occurred when either drug was injected at 0 HALO. The largest Vdi and the longest elimination were however observed at 8 HALO for CBDCA and 16 HALO for I‐OHP. No consistent relationship was found for both Pt complexes with regard to circadian changes in blood pharmacokinetics and in target organ toxicities.The major pharmacokinetic differences between CBDCA and I‐OHP were related to both protein binding and RBC handling.
The bioavailability of diclofenac from enteric coated products in healthy volunteers with normal and artificially decreased gastric acidity
Authors: Van Gelderen Marjet E. M. , Olling Martin , Barends Dirk M. , Meulenbelt Jan , Salomons Peter , Rauws Adalbert G. 
Published: October 2006

AbstractThe relative bioavailability of four monolithic enteric coated (MEC) diclofenac products was compared in 16 healthy volunteers. Only one generic product was fully bioequivalent with the reference product Voltaren with regard to AUC, Cmax, and tlag. Two products showed significant differences in tlag.In a second experiment with eight volunteers the influence of increased gastric pH (ranitidine treatment) on the two mutually most differing products was studied. They showed equivalence in AUC, but not in Cmax. Analysis of tlag suggests that the product with the low tlag disintegrates within the non‐acid stomach, whereas the product with the long tlag passes the non‐acid stomach intact.Several in vitro dissolution tests were conducted. The European Pharmacopeia test did not detect any differences between the products. At pH 5, both with and without mechanical stress, only the product with the shortest tlag released diclofenac. The in vivo results were best predicted by the in vitro dissolution tests performed at several fixed pH values with mechanical stress.
The estimation of the plasma free fraction of cyclosporine in rabbits and heart transplant patients: The application of a physiological model of renal clearance
Authors: Shah Ajit K. , Brundage Richard C. , Lake Kathleen D. , Sawchuk Ronald J. 
Published: October 2006

AbstractWe estimated the free fraction (fu) of cyclosporine (CyA) in the plasma from concentrations of CyA in urine (Cu) and plasma (Cp), urine flow rate (UF), and glomerular filtration rate in rabbits and in heart transplant patients. Following intravenous administration of CyA (5–30 mg kg−1) in ten NZW rabbits and oral administration of CyA (4.8–12.1 mg kg−1) in nine heart transplant patients, CyA concentrations in urine and plasma were measured by HPLC. The ratios of Cu to Cp and UF data were fitted to a physiological model of renal clearance using NONMEM. The free fraction of cyclosporine in the rabbits and the heart transplant patients was 0.0122 and 0.14, respectively. Because of the relatively low permeability of CyA across the tubular epithelium, no apparent equilibrium between Cu and Cp at any urine flow rate was reached and, therefore, the Cu to Cp ratio will not be equal to fu.
Disposition kinetics of hepp in rats after intravenous, oral, and intraperitoneal administration. Correlation of plasma and brain levels with the anticonvulsant effects
Authors: Gómez Lisbeth E. , Cueva‐Rolón Rafael , Lehmann F. Pedro A. 
Published: October 2006

AbstractD, L‐3‐hydroxy‐3‐ethyl‐3‐phenylpropanamide (HEPP) is a synthetic drug with anticovulsant effects in a variety of seizure models. HEPP pharmacokinetics was studied after single 50 mg kg−1 intravenous (IV), intraperitoneal (IP), and oral (PO) administration in male albino Wistar rats. The plasma concentration against time curves showed a biphasic decay pattern with a similar distribution phase and the same terminal rate constant (β = 0.22 h−1) by all three routes. The apparent volume of distribution at steady state (VSS = 0.80 L kg−1) indicates that HEPP is extensively distributed in extracellular tissues. This finding agrees very well with its low binding to plasma protein (mean bound fraction = 19.3 ± 1.1%). The systemic clearance (Cl) was very low (3.30mL min−1 kg−1). The bioavailability after IP and PO administration was 0.80 and 0.60 respectively. In the pharmacokinetic‐pharmacodynamic studies a direct relationship was found between the protective effect of HEPP against pentylenetetrazole (PTZ) induced seizures and its concentration in plasma and/or brain. The concentrations at half‐maximal effect (EC50) with 95% confidence interval (Cl) were 70.6 (66–75.5) μg mL−1 in serum and 60.1 (55.4–65.1) μg g−1 in brain. There was a rapid uptake of HEPP into the brain, and after the distributive phase, the disappearances in plasma and brain were almost parallel [Cserum = 109 e−0.25t, r2 = 0.95; Cbrain = 38 e2.53t + 91 e−0.21t, r2 = 0.93], with a Cbrain/Cplasma ratio of 1.1.
Plasma lipoproteins as targeting carriers to tumour tissues after administraion of a lipophilic agent to mice
Authors: Tokui Taro , Kuroiwa Chitose , Muramatsu Shigeki , Tokui Yoko , Sasagawa Kazuhiko , Ikeda Toshihiko , Komai Toru 
Published: October 2006

AbstractWe synthesized 14C‐warfarin hexadecyl ether (14C‐WHE) by addition of a palmityl moiety to the hydroxyl group at the 4‐position of 14C‐warfarin, a compound known to bind to serum albumin. 14C‐WHE preferentially bound to the lipoproteins, low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL), in mouse plasma both in vitro and in vivo. 14C‐Warfarin mainly concentrated in the liver immediately after intravenous administration to mice bearing M5076 sarcoma, and was found at only low concentrations in other tissues including the tumour. 14C‐WHE highly distributed to the tumour, in other tissues including the tumour. 14C‐WHE highly distributed to the tumour, adrenal, and spleen, as well as the liver. These tissues coincided with those in which human 125I‐LDL was vigorously incorporated. The results indicate that chemical modification of an agent, giving it high lipophilicity, will enable it to bind to lipoproteins after intravenous administration. These modifications raise the possibility of lipoproteins as endogenous targeting carriers into tumour cells, which have high LDL‐receptor activity.
Pharmacokinetics of amoxicillin coadministered with a saline‐polyethylene glycol solution in healthy volunteers
Authors: Padoin C. , Tod M. , Brion N. , Louchahi K. , Le Gros V. , Petitjean O. 
Published: October 2006

AbstractThe pharmacokinetics of orally administered amoxicillin were investigated in 12 healthy volunteers in a crossover design. They received either a placebo or a saline—polyethylene glycol solution (SPG) for 4 d, the last dose being given simultaneously with 1 g amoxicillin; blood samples were drawn for the next 12 h. Amoxicillin kinetics were similar in the two treatments but small differences in some pharmacokinetic parameters reached significance. The mean±SD area under the curve was lower with SPG (43.8±6.8 against 47.8±8.2 mg h L−1, p<0.05) but the treatments were equivalent according to Westlake's test (95% confidence interval = 14.95%). Analysis of SPG against placebo amoxicillin absorption kinetics after fitting the data to a Weibull model revealed a longer duration of the absorption, a slower rate of absorption, and a different shape of the curve. No clinical consequences are expected from these minor variations but possible mechanisms could be relevant to other drugs.
The effect of food on the absorption of 14C‐SDZ FOX 988, an antidiabetic agent, in healthy human volunteers
Authors: Lau David T.‐W. , Kalafsky G. , Tse Francis L. S. 
Published: October 2006

AbstractThe objective of this study is to examine the effect of food on oral absorption of SDZ FOX 988 (FOX 988), an antidiabetic agent, and circulating levels of its active metabolite, SDZ 53–450 (53–450). Sixteen normal volunteers received a single 10 mg dose of 14C‐FOX 988, either as gelatin capsules or in a suspension (0.5% CMC). For subjects receiving each formulation, four subjects received a meal, consisting of 50% fat by calories, immediately following dosing, while the other four received the same meal at 2 h post‐dose. Serial blood, urine, and fecal samples were collected for 120 h and analyzed for total radioactivity. Blood concentrations of 53–450 were analyzed using an HPLC–UV method. Concomitant administration with food increased the extent of FOX 988 absorption from either suspension or capsule, as shown by an increase in AUC and in urinary recovery of radioactivity. Blood concentrations of 53–450 were only detected in subjects receiving food at dosing. No difference in absorption was observed between the capsule and the suspension. Results from this study showed that oral absorption of FOX 988 is enhanced by co‐administration of food in normal volunteers.
Pharmacokinetic analysis of diethylcarbonate prodrugs of ibuprofen and naproxen
Authors: Samara Emil , Avnir David , Ladkani David , Bialer Meir 
Published: October 2006

AbstractThe pharmacokinetics of ibuprofen diethylcarbonate (ibudice) and naproxen diethythylcarbonate (napdice), two new diethylcarbonate prodrgs of ibuprofen and naproxen, was investigated in dogs. The rationale for the development of ibudice and napdice was that esterification of the carboxylic moiety of the parent compounds would suppress gastrotoxicity without adversely affecting their anti‐inflamatory activity. In addition the biotransformation of the prodrugs to the parent compounds may be utilized to achieve rate and time controlled drug delivery of the active entities. Following oral administration the diethycarbonate esters were rapidly biotransformed to the parent compounds and no ibudice or napdice was detected in the plasma. The relative bioavailability of ibuprofen and naproxen, following oral administration of ibudice and napdice, was 96% and 74%, respectively, and the rate of absorption was not significantly different from that obtained following oral dosing of the parent compound. Stability studies in gastric and intestinal juice showed that, unlike napdice, ibudice was stable in gastric juice, with both prodrugs undergoing rapid biotransformation to their parent compounds in intestinal juice. This rapid conversion led to the lack of sustained release performance following oral administration of ibudice or napidice.
Disposition of [3H]fluvastatin following single oral doses in beagle dogs and rhesus monkeys with bile fistulae
Authors: Tse Francis L. S. , Dain Jeremy G. , Kalafsky Gaetana 
Published: October 2006

AbstractThe disposition of [3H]fluvastatin was examined following single oral doses in dogs (12.4 mg kg−1) and monkeys (0.48 45.5 mg kg−1) with bile fistulae. Serial plasma and complete urine, feces, and bile were collected at designated intervals for 3 or 4 d, and were analyzed for total radioactivity and unchanged fluvastatin. In the dog, peak radioactivity concentrations (Cmax) averaged 7260 ng equiv. mL−1 and the mean time to peak (tmax) was ∼ 9 h. In the monkey, the mean radioactivity tmzx values were ∼ 5 and 13 h following the low and high doses, the respective Cmax values being 116 and 10400 ng equiv. mL−1. The mean AUC of total radioactivity was proportional to the dose while that of fluvastatin was overproportional to dose, suggesting dose indepedent absorption but saturable first‐pass effect. The AUC ratio of unchanged fluvastatin versus total radioactivity was approximately 63% in the dog, and 9% and 13% for the low and high doses, respectively in the monkey. The bile was the major excretory route of radioactivity (dog, 56%; low‐dose monkey, 73%; high‐dose monkey, 69%) whereas the renal pathway accounted for < 5% of the dose in both species. Approximately 12% of the biliary radioactivity in the dog was due to intact fluvastatin, compared with 0% and 7.5% after the low and high doses in the monkey. These results showed a smaller extent of fluvastatin metabolism in the dog than in the monkey, and suggested that metabolism in the monkey was saturable in the dose range studied.