bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of a new orally potent tripeptide HIV‐1 protease inhibitor (anti‐aids drug) based on pharmacokinetic characteristics in rats after intravenous and intraduodenal administrations
Authors: Kiriyama A. , Mimoto T. , Kisanuki S. , Kiso Y. , Takada K. 
Published: October 2006

AbstractRecently, a series of KNI compounds such as KNI‐227 and KNI‐272 has been synthesized and shows potent and selective HIV‐1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI‐227 and KNI‐272 in rat plasma and examined the pharmacokinetic characteristics in rats after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailabilities of these new anti‐AIDS drugs. After i.v. administration of KNI‐227, 10.0mg kg−1, the mean terminal elimination half‐life, t1/2λz, was 0.808±0.161(SE)h, the total body clearance, CLtot, was 11.7±3.3 ml min−1 and the distribution volume at steady state (Vd,ss) was 1410.460 ml kg−1. On the other hand, after i.v. administration of KNI‐272, 10.0mg kg−1, t1/2λz was 2.86±0.78 h, CLtot was 15.3±1.4 ml min−1 and Vd,ss was 3440.670 ml kg−1. In the case of the i.d. administration of drugs, the mean peak plasma concentrations, Cmax, of KNI‐227 and KNI‐272 were 0.374±0.110μg ml−1 and 0.900±0.093 μg ml−1, respectively. The bioavailabilities (BA) of KNI‐227 and KNI‐272 to infinity, BA(0‐∞), were 5.90% and 42.3%, respectively. As compared with the lead compound, KNI‐174, the BA of KNI‐272 was improved about 10 times. Although the anti‐AIDS virus activity of these two drugs has not been investigated in vivo, KNI‐272 is expected to be a better candidate for oral anti‐AIDS therapies.
Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulations of diltiazem in healthy volunteers
Authors: Guimont Sonia , Landriault Hélène , Klischer Keith , Grace Michael , Lambert Chantal , Caillé Gilles , Gossard Denis , Russell Anthony , Raymond Manon , Hutchings Edna , Spénard Jean 
Published: October 2006

AbstractCardizem®SR and Bi‐Tildiem® were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross‐over randomized study, we assessed whether these two sustained‐release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty‐four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high‐performance liquid chromatographic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash‐out. Pharmacokinetics showed statistically significant (p <0.01) differences in AUC0–12 with means (±SD) of 519.2(±172.8) and 429.6(±147.2)ng h ml−1, AUC0–36 of 835.6(±281.6) and 730.9 (±271.5)ng h ml−1 and Cmax of 89.1(±30.3) and 61.1(±21.2) ng ml−1 for Cardizem®SR and Bi‐Tildiem®, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (±SD) change in AUC0–12 of −13.6(±20.8) and +8.4(±31.7) mm Hg h (p = 0.0135) and in AUC0–24 of −33.0(±43.7) and −0.3(±59.2) mm Hg h (p = 0.0463) for Cardizem®SR and Bi‐Tildiem®, respectively. These findings suggest that assessment of efficacy of sustainedrelease formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.
The effect of food on the relative bioavailability of fadrozole hydrochloride
Authors: Choi R. Leslie , Sun Jim X. , Kochak Gregory M. 
Published: October 2006

AbstractThe effect of food on the pharmacokinetic disposition of fadrozole hydrochloride was evaluated in nine healthy male and female volunteers. Single 12 mg doses of fadrozole were orally administered to subjects immediately following a standardized meal or after fasting for 12 h, in a randomized crossover design. No statistically significant treatment differences were detected for the pharmacokinetic parameters AUC and half‐life. Cmax was significantly reduced by 15% for the fed treatment relative to the fasted treatment, and tmax was delayed by 39%. These findings indicate that the concomitant ingestion of food with fadrozole delays the gastric emptying and/or absorption of fadrozole, but has no effect on the extent of absorption.
The effect of chloroquine on the pharmacokinetics and metabolism of praziquantel in rats and in humans
Authors: Masimirembwa C. M. , Naik Y. S. , Hasler J. A. 
Published: October 2006

AbstractIt is likely that a proportion of people treated with the anti‐schistosomicidal drug praziquantel (PZQ) is also taking other drugs such as chloroquine (CHQ), a widely used anti‐malarial. The effect of CHQ on the pharmacokinetics and metabolism of PZQ in rats and in humans was therefore studied. CHQ decreased the bioavailability of PZQ and reduced its maximum serum concentrations to a significant extent in rats and in humans. The clearance was increased to a statistically significant extent in rats but not in humans because of the wide interindividual variation. The effect of CHQ on PZQ pharmacokinetics was unexpected since drugs that inhibit hepatic drug metabolism usually increase the bioavailability of PZQ. We found that CHQ inhibits non‐competitively the metabolism of PZQ to its major metabolite, 4‐hydroxy‐praziquantel, with a Ki of 1.65 mM in rat hepatic microsomes. Maximum concentrations attained by CHQ in serum, however, are low compared to the Ki value and significant inhibition is therefore unlikely in vivo. The explanation for CHQ's effect on the pharmacokinetics of PZQ may be due to other effects of CHQ rather than to a direct effect on drug‐metabolizing enzymes.
The pharmacokinetics and metabolism of DuP 532, a non‐peptide angiotensin II receptor antagonist, in rats and dogs
Authors: Wong Y. N. , Holm K. A. , Burcham D. L. , Huang S.‐M. , Quon C. Y. 
Published: October 2006

AbstractDuP 532, 2‐propyl‐4‐pentafluoroethyl‐1‐{[2′‐(1H‐tetrazol‐5‐yl)biphenyl‐4‐yl] methyl} imidazole‐5‐carboxylic acid, is an orally active, non‐peptide angiotensin II (AII) receptor antagonist. DuP 532 is more potent and longer acting than losartan, another AII receptor antagonist currently undergoing phase III clinical trials. The pharmacokinetics and the effect of the salt form on the bioavailability of DuP 532 were determined in rats and dogs. In rats, the absolute oral bioavailability and half‐life averaged 8·0% and 3·5 h, respectively, after the sodium bicarbonate solution and 7·6% and 3·6 h, respectively, after the methyl cellulose suspension. In dogs, the absolute oral bioavailability averaged 13.4% after the sodium bicarbonate solution and 11·9% after hard gelatin capsules containing the neat powder. The data demonstrated that there were no differences in bioavailability between the free acid and the sodium salt of DuP 532 after oral administration to rats and dogs.The in vitro metabolism of 14C‐DuP 532 was evaluated with rat, dog, and human liver microsomes. HPLC analyses with UV and radiochemical flow detection showed that recovery of DuP 532 was greater than 99%, suggesting that there was little if any metabolism by liver microsomal enzymes. Therefore, the low oral bioavailability in rats was probably due to poor absorption of DuP 532 from the GI tract rather than extensive metabolism.
Comparative in vitro and in vivo bioavailability of naproxen from tablet and caplet formulations
Authors: Charles B. G. , Mogg G. A. G. 
Published: October 2006

AbstractA 500 mg dose of naproxen in a caplet formulation (product A) or a tablet (Naprosyn 500, product B) was administered to 14 fasting healthy subjects on two separate occasions, separated by a 1–2 week washout period in an open, randomized crossover. Blood samples were drawn periodically and plasma naproxen concentrations measured by HPLC. The median time Tmax to reach peak concentration for product A was shorter than that for product B (1·025 h versus 1·5 h) but A and B were similar with respect to median peak plasma concentration Cmax (77·9 mg 1−1 versus 71·4 mg 1−1), and average area AUC0–∞ under the plasma concentration—time curve (1210·2 mg 1−1 h versus 1211·0 mg 1−1 h). In vitro parameters (A versus B) of mean dissolution time MDT (5·03 min versus 15·0 min), and time for 70% dissolution T70 (6·67 min versus 20·2 min), differed significantly.
Glucocorticoid‐dextran conjugates as potential prodrugs for colonspecific delivery: Steady‐state pharmacokinetics in the rat
Authors: McLeod Andrew D. , Tolentino Lorna , Tozer Thomas N. 
Published: October 2006

AbstractChronic colitis, e.g., ulcerative colitis and Crohn's disease, is presently treated with glucocorticoids and other antiinflammatory agents. Side‐effects limit chronic glucocorticoid therapy. The dose, and consequently the side‐effects, may be reduced by using prodrugs that selectively deliver drug to the colon. We previously synthesized glucocorticoid‐dextran conjugates in which dexamethasone was attached to dextran (weight‐average molecular weight = 72 600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, dexamethasone‐succinate‐dextran and dexamethasone‐glutarate‐dextran were administered to two groups of male Sprague‐Dawley rats by intragastric infusion. In two additional groups, disodium dexamethasone phosphate and dexamethasone hemisuccinate were each administered by subcutaneous infusion. In a fifth group, dexamethasone was administered by intragastric infusion. All groups were infused for sufficient time for steady state to be achieved. Colon‐specific delivery was quantified using a drug‐delivery index (DDI) in which steady‐state dexamethasone concentrations in the cecum and colon were compared with those measured in blood after separate administrations of dexamethasone and dexamethasone‐dextran conjugate. The colonic DDI values for dexamethasone‐succinate‐dextran and dexamethasone‐glutarate‐dextran were approximately seven and four, respectively. These values were a result of higher tissue concentrations and lower blood concentrations of dexamethasone after intragastric administration of the conjugates compared to subcutaneous and intragastric administration of dexamethasone. The pharmacokinetics of methyl‐prednisolone was also investigated after subcutaneous infusion. Observed cecal and colonic tissue‐to‐blood ratios of 19:1 and 12:1, respectively, showed that this drug is extensively delivered to the large intestine even after subcutaneous administration.
The lack of effect of smoking on the pharmacokinetics and pharmacodynamics of adinazolam and N‐demethyladinazolam
Authors: Chambers J. H. , Fleishaker J. C. 
Published: October 2006

AbstractThe pharmacokinetics and pharmacodynamics of adinazolam and N‐demethyladinazolam (NDMAD) were evaluated in twelve healthy non‐smokers (NS) and twelve smokers (S, ⩾ 20 cigarettes/day) following a single 60 mg dose of adinazolam mesylate sustained‐release tablets in an open‐label, parallel‐group design. Venous blood samples were collected for up to 36 h following drug administration and assayed for adinazolam and NDMAD by HPLC. Urine samples were also collected and assayed for NDMAD by HPLC. Psychomotor performance was measured using the Neurobehavioral Evaluation System. No significant differences were observed in adinazolam oral clearance (51.8±25.8 versus 48.2±14.01 h−1) or peak adinazolam plasma concentrations (Cmax) (93.3±31.8 versus 90.4±18.0 ng ml−1) between groups. NDMAD AUC (2541.457 versus 2798±447 ng h ml−1) and Cmax (173±30.3 versus 175±26.9 ng ml−1) did not differ significantly between groups. NDMAD renal clearance was significantly lower in smokers than non‐smokers (8.7±0.7 versus 10.7±2.71 h−1; p<0.05), but the clinical significance of this observation is unclear. Marginally significant differences were seen between groups in the symbol‐digit substitution and digit span (forward) tasks. The results suggest that smoking has little effect on adinazolam and NDMAD pharmacokinetics or psychomotor effects but that smoking may slightly decrease renal clearance of NDMAD.
An algorithm and computer program for calculating the mean transit time and distribution rate parameters of generated metabolites undergoing linear tissue distribution and linear or non‐linear central elimination
Authors: Cheng Haiyung , Yu Chi , Jusko William J. 
Published: October 2006

AbstractA method is described for calculating the mean transit time and distribution rate parameters of a generated primary metabolite undergoing linear distribution and linear or non‐linear central elimination, and of catenary metabolites with any precursor order. It is also applicable to a drug and its interconversion metabolite and does not require separate administration of the metabolite. The method allows steady‐state volume of distribution and distribution clearance of a metabolite to be calculated, provided that the central volume of distribution of the metabolite is known. An algorithm and computer program to implement the proposed method are presented. The calculations require the plasma concentration versus time curves of the metabolite and its precursor. The method is applied to both published and simulated data.
Pharmacokinetics of a novel retinoid AGN 190168 and its metabolite AGN 190299 after intravenous administration of AGN 190168 to rats
Authors: Hsyu Poe‐Hirr , Bowen Beta , Tang‐Liu Diane 
Published: October 2006

AbstractThe pharmacokinetics of AGN 190168, a novel synthetic retinoid, and its major metabolite, AGN 190299, in rat blood after intravenous administration was investigated. Approximately 4.4 mg kg−1 (high dose) or 0.49 mg kg−1 (low dose) of AGN 190168 was administered to rats via the femoral vein. Blood was collected from the femoral artery at various time points during an 8 h period. Blood concentrations of AGN 190168 and AGN 190299 were determined by a specific and sensitive high‐pressure liquid chromatographic (HPLC) method.AGN 190168 was rapidly metabolized in rats. The only detectable drug‐related species in the blood was AGN 190299. Therefore, only pharmacokinetics of AGN 190299 were calculated. Elimination of AGN 190299 appeared to be non‐linear after administration of the high dose, and linear after administration of the low dose. The maximum elimination rate (Vmax) and the concentration at half of the Vmax (km), as estimated by a Michaelis—Menten one‐compartment model, were 7.58 ± 2.42 μg min−1 (mean ± SD) and 6.10 ± 1.58 μg mL−1, respectively. The value of the area under the blood concentration time curve (AUC) was 9.54 ± 1.68 μg h mL−1 after administration of the high dose and 0.594 ± 0.095 μg h mL−1 after administration of the low dose. The clearance value was 7.79 ± 1.20 mL min−1 kg−1 after the high dose, statistically significantly different from that after the low dose (p < 0.05), 14.0 ± 2.2 mL min−1 kg−1. The terminal half‐life (t1/2) was 1.25 ± 0.74 h for the high‐dose group and 0.95 ± 0.16 h for the low‐dose group.Study results demonstrate rapid systemic metabolism of AGN 190168 to AGN 190299, non‐linear pharmacokinetics of AGN 190299 after the 4.4 mg kg−1 dose, and the lack of difference in disposition profiles between sexes after intravenous administration of AGN 190168 to rats.
Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel
Authors: Sioufi A. , Pommier F. , Boschet F. , Godbillon J. , Lavoignat D. , Salliere D. 
Published: October 2006

AbstractThe percutaneous absorption of diclofenac was studied in ten healthy volunteers treated with Emulgel containing 1.16% diclofenac diethylammonium for 8 d as follows: a single application of 5 g Emulgel on days 1 and 8, and two applications d−1 on days 2–7. Plasma concentration profiles of unchanged diclofenac and urinary concentrations of total diclofenac and metabolites (sum of free and conjugated) were determined.High inter‐individual variations in plasma and urine data were recorded, due probably to the permeability and the hydration of the skin. Steady state was reached after 2 d of twice‐daily administration. Plasma concentrations were low but remained in the range 10–50 nmol L−1 over the full day for most of the subjects, indicating prolonged absorption from the application site.
Relative bioavailability of four controlled‐release nifedipine products
Authors: Schall R. , Müller F. O. , Hundt H. K. L. , Duursema L. , Groenewoud G. , Van Dyk M. , Van Schalkwyk A. M. C. 
Published: October 2006

AbstractFour controlled‐release nifedipine products were investigated in two clinical studies. In study 1, 22 healthy male volunteers took part in an open, multiple‐dose, randomized, crossover study to determine the relative bioavailablity of two 10 mg controlled‐release nifedipine tablet (Adalat® Retard, Bayer), administered 12 hourly, and one 20 mg controlled‐release nifedipine tablet (Adalat® Retard, Bayer) administered 12 hourly. In study 2, 24 healthy male volunteers took part in an open, multiple‐dose, randomized, three‐period, crossover study to determine the relative bioavailability of (i) two 30 mg nifedipine gastro‐intestinal therapeutic system (GITS) tablets (Adalat® XL, Bayer) administered once daily; (ii) one 60 mg nifedipine GITS tablet (Adalat® XL, Bayer) administered once daily; and (iii) one 20 mg plus one 10 mg nifedipine controlled‐release tablet (Adalat® Retard, Bayer), administered 12 hourly. In both studies detailed pharmacokinetic data, in particular with respect to the controlled‐release characteristics of the different formulations, were collected.Results of both studies indicate that all nifedipine products investigated are bioequivalent with respect to the extent of absorption of nifedipine. The nifedipine GITS products (Adalat® XL) have better controlled‐release properties than the Adalat® Retard product, and are suitable for once‐a‐day administration.
The influence of food on the disposition of the antiepileptic oxcarbazepine and its major metabolites in healthy volunteers
Authors: Degen P. H. , Flesch G. , Cardot J.‐M. , Czendlik C. , Dieterle W. 
Published: October 2006

AbstractThe effect of food on the pharmacokinetics of the antiepileptic oxcarbazepine (OXC) was investigated in healthy volunteers. Six healthy male volunteers were treated with single peroral doses of 600 mg of oxcarbazepine (Trileptal®) after overnight fasting or a fat‐ and protein‐rich breakfast. Mean (± SD) areas under the plasma concentration—time curves (AUC) of the major component in plasma, the active monohydroxy metabolite (MHD), which is responsible for the therapeutic effect in man, were 672 (25) μmol L−1 h when given to the fasted volunteers and 780 (31) μmol L−1 h (p = 0.042) when given after a substantial breakfast. Mean (± SD) maximum concentrations (Cmax) were 25.5 (4.8) μmol L−1 when given to the fasted volunteers and 31.4 (5.3) μmol L−1 (p = 0.025) when given after breakfast. Thus, the average AUC was increased by 16% and Cmax by 23% when oxcarbazepine was given with food. The times at which Cmax was reached (tmax) as well as the terminal half‐lives were not influenced by concomitant intake of food. The tolerability was the same whether oxcarbazepine was given before or after food in healthy volunteers. The slight effect of food on the kinetics of oxcarbazepine should be of little therapeutic consequence.
Griseofulvin absorption from different sites in the human small intestine
Authors: Gramatté T. 
Published: October 2006

AbstractThe site‐dependent small‐intestinal absorption pattern of griseofulvin was investigated in man. Griseofulvin was chosen as a model substance having extremely low water solubility and moderate lipid solubility. A conventional steady‐state perfusion technique (triple‐lumen tubing system with a 20 cm test segment) was applied. Dissolved griseofulvin (10.0 mg L−1) was perfused (10 mL min−1) during 160 min into different parts of the small intestine with the middle of the test segment between 85 cm and 270 cm beyond the teeth. Each of the ten healthy volunteers was examined twice with the test segment localized in different regions to allow for intraindividual comparisons. Mean drug absorption rates calculated from intestinal aspirate concentrations were similar in the two intestinal parts (proximal, 15.0 ± 5.9 μg (20cm min)−1; distal, 16.2 ± 4.3 μg (20 cm min)−1; mean ± SD). Absorption rate was strongly correlated to the amount of griseofulvin offered to the test segment per unit time. Extrapolating these findings it follows that an amount of griseofulvin, once dissolved, would be absorbed completely (>99%) along 100 cm of the small intestine. A significant, positive correlation between the rate of transmucosal fluid transport and the absorption rate of griseofulvin was observed in the distal parts investigated.
The effect of the fat content of food on the pharmacokinetics and pharmacodynamics of SDZ FOX 988, an antidiabetic agent, in the dog
Authors: Lau David T.‐W. , Kalafsky G. , Aun Renee L. , Tse Francis L. S. 
Published: October 2006

AbstractSDZ FOX 988 (FOX 988) is being developed for the treatment of type II diabetes. The objective of this study was to examine the effect of the fat content of food on the pharmacokinetics and pharmacodynamics of FOX 988 following oral administration in the dog. In a randomized, cross‐over design, four dogs received a single 10 mg kg−1 dose of 14C‐FOX 988 suspension concomitantly with food containing 10% fat or 40% fat, or with the 10% fat food at 4 h post‐dose. Serial blood, urine, and fecal samples were collected for 96 h and analyzed for total radioactivity. Blod concentrations of 53–450, the active metabolite of FOX 988, were also determined. Serum concentrations of β‐hydroxybutyrate and glucose, pharmacological markers for the antidiabetic effects, were measured serially for 24 h after dosing. The animals receiving the low‐fat meal at dosing and at 4 h post‐dose exhibited similar extents of absorption, as shown by similar AUC values and urianry radioactivity recovery. Administration of the high‐fat meal at dosing significantly enhanced the absorption of FOX 988 and resulted in high blood concentrations of 53–450. However, no significant differences in the pharmacological activity of the drug were observed among the three treatments.
Uptake and biodisposition of 2‐ylcyanamide‐1,3,4‐thiadiazole (LY217896) by red blood cells
Authors: Bonate Peter L , Peyton Albert 
Published: October 2006

AbstractIn man, 14C‐2‐ylcyanamide‐134‐thiadiazole (LY217896) accumulates into red blood cells (RBCs) where it is rapidly metabolized. Both in man and ex vivo, within a few hours of administration of 14C‐LY217896 at least two intracellular metabolites were detected within the RBCs using HPLC. These metabolites were never detected extracellularly. After 24 h no detectable radioactivity was found in the plasma and all the radioactivity was detected within the cellular fraction. All radioactivity was identified as a single peak within the RBCs, indicating the metabolite(s) to be highly polar compared to LY217896. Parent LY217896 was never detected within the RBCs at any time point, suggesting transport, either by diffusion or a carrier mediated mechanism, was the rate limiting step. Due to the nature of the preparation it was impossible to separately characterize uptake and biotransformation. Nevertheless, uptake/biotransformation was found to be temperature sensitive, sodium independent, and energy dependent. Both niacin and vitamin B6, but not nicotinamide, competitively blocked the uptake and subsequent intracellular metabolism of LY217896.