bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects
Authors: De Vries M. H. , Van Harten J. , Van Bemmel P. , Raghoebar M. 
Published: October 2006

AbstractThe pharmacokinetics of fluvoxamine after single oral administration of 25, 50, and 100 mg fluvoxamine maleate was studied in a three‐way cross‐over study in 12 healthy male subjects. Fluvoxamine was administered orally in a solution. For doseproportionality, AUC, and Cmax‐dose relationships were evaluated by linear regression. Plasma concentrations increased in a linear dose‐dependent manner in the dose range between 25 and 100 mg; t1/2 and Tmax showed no significant differences among treatments. Fluvoxamine was well tolerated.
Nonlinear elimination and hepatic concentration of conjugation‐ metabolite of valproate in guinea‐pigs
Authors: Yu Hsiu‐Ying , Wu Mei‐Sue , Shen Yu‐Zen 
Published: October 2006

AbstractThe plasma clearance and metabolic rate characteristics of valproic acid (VPA) were studied using guinea‐pigs placed on various (0.08‐9 μmol ml−1 = 11–1303 μg ml−1) steady‐state plasma concentrations (Css) by constant intravenous (i.v.) infusion. The total clearance (CL) was significantly decreased at plasma concentration of 0.61 μmol ml−1 (88 μg ml−1). The metabolic clearance of VPA was apparently biphasic. The maximum metabolic rate (Vmax) and the Michaelis‐Menten constant (Km) for the primary (Vmaxl, Kml) and the secondary (Vmax2, Km2) pathways were Vmaxl = 1.52 μmol min −1kg−1, Kml = 0.15 μmol ml−1, Vmax2 = 24.98 μmol min −1 kg−1 and Km2 = 11.70 μmol ml−1, respectively. The Kml value was within clinical therapeutic concentration range. The formation of conjugated VPA (cjVPA) metabolite in liver was shown to be saturable. Plasma protein binding of VPA was also nonlinear. The dose‐dependent decrease in metabolic clearance was counterbalanced by the increased unbound fraction (fu), resulting in a relatively constant apparent clearance of VPA over a wide concentration range. The hepatic concentration of VPA was not significantly different from the plasma unbound concentration, again over a wide concentration range. The biliary and hepatic concentrations of VPA were not significantly different; but the concentration ratio of cjVPA in bile compared with that of VPA in liver decreased against hepatic concentration of VPA, which suggests a saturable conjugation rate. The Km value estimated from hepatic cjVPA production as a function of plasma VPA concentration was comparable with the Kml value. These results implied that the primary metabolic parameters may describe the conjugation pathway which is nonlinear within the clinical therapeutic concentration range.
Pharmacokinetics and bioavailability of medroxyprogesterone acetate in the dog and the rat
Authors: Smith D. , Enever R. , Dey M. , Latta D. , Weierstall R. 
Published: October 2006

AbstractMedroxyprogesterone acetate (MPA) has been administered to rats and dogs. Dogs received single oral doses of 2.5, 5, and 10 mg MPA and a single intravenous dose of 1 mg MPA. Rats received single oral doses of 0.2, 1, 5, and 20 mg kg−1 MPA and multiple oral doses (14 daily doses) of 0.2, 5, and 20 mg kg−1 MPA. Dog plasma MPA levels from the intravenous dose were characterized by a triexponential decay with disposition half‐lives of 0.3, 1.8, and 21.6 h. A Loo‐Riegelman analysis of the dog plasma MPA levels from oral doses indicated absorption was not a simple first‐order process. The Weibull Function was used to characterize the absorption kinetics of MPA. The oral absorption of MPA in dogs appears to be dose‐linear over the dosage range studied, and the absolute bioavailability was estimated at 27 per cent. Rat plasma MPA levels from single and multiple oral doses were analyzed by a non‐compartmental approach. AUC and Cmax values were not dose‐linear over the dosage range studied; indicative of the self‐induced metabolism of MPA. Exposure of similar dosages of MPA to both the rat and the dog resulted in similar plasma profiles and pharmacokinetics.
Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase isozymes by repeated cyanamide administration: Pharmacokinetic‐pharmacodynamic relationships
Authors: Piera Juan Pruñonosa , Obach Rosendo , Sagristá Maria Luisa , Bozal Jorge 
Published: October 2006

AbstractThe inhibition of rat hepatic mitochondrial aldehyde dehydrogenase (ALDH) isozymes was studied in apparent steady‐state conditions after repeated intra‐peritoneal cyanamide administration. The low‐Km mitochondrial ALDH isozyme was more susceptible to cyanamide‐induced inhibition (DI50 = 0.104 mg kg−1) than the high‐Km isozyme (DI50 = 8.52 mg kg−1), with almost complete inhibition occurring at 0.35 mg kg−1 total cyanamide administered for the low‐Km isozyme. The relationships between plasma and liver cyanamide concentrations and the inhibition of high‐Km ALDH were established by means of the sigmoid Imax model. The effect of dosing rate on the plasma concentration of cyanamide at apparent steady‐state showed non‐linearity, indicating that clearance or first‐pass metabolism of cyanamide during its absorption after intraperitoneal administration did not remain constant throughout the range of doses studied.
The use of a nonlinear absorption model in the study of ascorbic acid bioavailability in man
Authors: Piotrovskij V. K. , Kállay Z. , Gajdoš M. , Geryková M. , Trnovec T. 
Published: October 2006

AbstractA two‐compartment disposition model of ascorbic acid (AA) pharmacokinetics with saturable and time‐constrained intestinal absorption was developed. The model was fitted to pharmacokinetic data obtained after oral administration to nine healthy volunteers of two effervescent dosage forms differing in AA content: Celaskon 60 mg (CK60) and Celaskon 500 mg (CK500). It was demonstrated that in the case of CK500 less than 30% of the dose was absorbed as compared with CK60. Parameters of the AA nonlinear absorption kinetics were assessed by simultaneous fitting of mean concentration—time data for both doses and placebo. The relatively short duration of absorption found (3.2 h) can explain the failure of past attempts to increase the AA bioavailability using sustained‐release dosage forms. Model simulation showed that the ingestion of 60 mg with 3–4 h intervals is optimal for maximal bioavailability of AA.
Toxicokinetic approach for evaluating respiratory depression effect of aminoglycoside antibiotics: Species differences in drug susceptibility
Authors: Komiya Izumi , Mitomi Nayu , Kuribayashi Takashi , Takata Hiromi 
Published: October 2006

AbstractThe respiratory depression effect of aminoglycoside antibiotics was studied by a toxicokinetic approach, and species differences in drug susceptibility were elucidated based on plasma concentrations. An allometric relationship was obtained between total body clearance of arbekacin, a novel aminoglycoside antibiotic, and animal body weight. The power was 0.714, less than unity, which means smaller animals have higher ability to eliminate the drug from the body and need higher doses to attain a certain steady‐state plasma concentration. When the infusion rate of arbekacin was altered, the total dose required to cause the toxicologic endpoint for respiratory depression (60 per cent loss of respiratory rates) changed greatly, but the plasma concentration of arbekacin at the toxicologic endpoint remained at almost a constant level. The concentration at the toxicologic endpoint was similar for all of the animal species examined and was 650–950 μg ml−1, even though the total dose required to cause the toxicologic endpoint varied greatly among the animal species. These findings suggest that the toxicologic effect compartment for respiratory depression is indistinguishable from the plasma compartment, and that species differences in the total dose are due to differences in pharmacokinetics of the drug, mainly in the total body clearance, but not to differences in intrinsic susceptibility to the drug.
Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans
Authors: Vree Tom B. , Van Den Biggelaar‐Martea Magdalena , Verwey‐Van Wissen Corrien P. W. G. M. , Vree Jeroen B. , Guelen Pieter J. M. 
Published: October 2006

AbstractThe aim of this investigation was to assess the pharmacokinetics of naproxen in 10 human subjects after an oral dose of 500 mg using a direct HPLC analysis of the acyl glucuronide conjugates of naproxen and its metabolite O‐desmethylnaproxen. The mean t1/2 of naproxen in 9 subjects was 24.7 ± 6.4 h (range 16 to 36 h). The t1/2 of 7.4 as found in subject number 10 must, therefore, be regarded as an extraordinary case (p <0.0153). Naproxen acyl glucuronide accounts for 50.8 ± 7.32 per cent of the dose, its isomerized conjugate isoglucuronide for 6.5 ± 2.0 per cent, O‐desmethylnaproxen acyl glucuronide for 14.3 ± 3.4 per cent, and its isoglucuronide for 5.5 ± 1.3 per cent (n = 10; 100 h collection period). Naproxen and O‐desmethylnaproxen are excreted in negligible amounts ( <1 per cent). Even though urine pH of the subjects was kept acid (range pH 5.0–5.5) in order to stabilize the acyl glucuronides, isomerization takes place in blood when the acyl glucuronide is released from the liver for excretion by the kidney. Binding to plasma proteins was measured as 98 per cent and 100 per cent, respectively for the unconjugated compounds naproxen and O‐desmethylnaproxen. Binding of the acyl glucuronides was less, being 92 per cent; for naproxen acyl glucuronide, 66 per cent for naproxen isoglucuronide, 72 per cent for O‐desmethylnaproxen acyl glucuronide and 42 per cent for O‐desmethylnaproxen isoglucuronide.
Bumetanide binding to normal albumins and to albumin in renal failure
Authors: Howlett M. R. , Auld W. H. R. , Murdoch W. R. , Skellern G. G. 
Published: October 2006

AbstractBinding of bumetanide, a loop diuretic, to partially purified albumins from renal failure patients (RF‐HA), and healthy subjects (N‐HA), human serum albumin (HSA) and defatted‐HSA (D‐HSA), was studied with equilibrium dialysis at a constant albumin concentration and various ligand concentrations.Binding parameters (n and K) were estimated from Scatchard plots and with a nonlinear two‐binding site model computer program, assuming two classes of independent sites. The binding capacities (n1K1) decreased in the order N‐HA>RF‐HA>D‐HSA>HSA. Computer estimates of K1 for the partially purified albumin preparations were not markedly different. However, the graphical estimate of K1 for N‐HA was greater than that for RF‐HA. When the degree of binding (r) was plotted as a function of the logarithm of the free bumetanide concentration, an asymptotic plateau was not observed, indicating that the protein binding sites were not saturated. Consequently, the calculated binding estimates may not adequately describe the binding of bumetanide.
Metabolism and disposition of EXP631—A novel antidepressant analgesic
Authors: Wong Y. N. , Burcham D. L. , Huang S.‐M. , Quon C. Y. 
Published: October 2006

AbstractEXP631, 4‐(3‐thienyl)‐α,α, 1‐trimethyl‐4‐piperidinemethanol hemi‐fumarate salt (I), is a centrally acting non‐opioid analgesic compound with monoamine uptake blocking properties. EXP631 has analgesic effects in several animal models. It is intended to be used for the treatment of moderate to moderately severe acute and chronic pain. To characterize the disposition of EXP631, the plasma levels of EXP631 were determined in rats and dogs after single intravenous and oral doses. In rats, EXP631 was rapidly absorbed following a single oral solution dose of 5–20 mg kg−1 with maximum plasma levels detected within 1.2 h post dose. The absorption was complete with an oral bioavailability of 92–131%. The pharmacokinetics was dose independent as measured by either Cmax or AUC values. In fasted dogs, EXP631 was absorbed rapidly and well (F = 81%) from an oral solution with the maximum concentration detected at 20 min post dose. In fed dogs, the absorption from capsules was slower (1.38 h) compared to the solution, but the absorption was complete (F = 115%). An N‐desmethyl metabolite (II) was found in both rat and dog plasma samples. The structure was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy and comparative chromatographic retention times. The metabolite is inactive as an analgesic.
Pharmacokinetics of intravenous and epidural ropivacaine in the rhesus monkey
Authors: Katz Jeffrey A. , Sehlhorst Constance S. , Thompson Gary A. , Denson Donald D. , Coyle Dennis , Bridenbaugh Phillip O. 
Published: October 2006

AbstractRopivacaine is a new long‐acting amide local anesthetic which is possibly less cardiotoxic than bupivacaine. The absorption and disposition of ropivacaine were characterized in six rhesus monkeys in an open two‐way crossover study following intravenous and epidural administration. For these studies, animals were anesthetized for placement of intravenous and intraarterial catheters. For the epidural studies, a PE‐10 catheter was also inserted 3 cm into the lumbar epidural space. After recovery from anesthesia, animals received ropivacaine 1 mg kg−1 intravenously over 1 min or 10 mg of ropivacaine epidurally (two 1 ml doses of 0.5, 5 min apart), and arterial blood samples were obtained over 5 h. Serum ropivacaine concentrations were determined by gas chromatography with NP detection. Concentration—time data following i.v. and epidural administration were fitted simultaneously. Initial parameter estimates were obtained by analyzing each route separately. Input rates and their corresponding extent of absorption were estimated using deconvolution.Mean (±SD) disposition parameters included: Vss = 1.11±0.198 1kg−1; CL = 0.711 ± 0.158 1 h−1 kg−1; t1/2,z = 2.07 ± 0.438 h. Mean (± SD) absorption parameters included: F1 = 0.506 ± 0.221; t = 0.060 ± 0.078 h; F2 = 0.444 ± 0.182; t = 6.45 ± 11.09h. Ropivacaine's biphasic absorption and bioavailability are similar to those of other amide local anesthetics. The biphasic absorption may be related to partitioning into fat or regional changes in blood flow induced by the drug.
Biotransformation and urinary excretion of 4‐substituted amphetamines in pregnant mice
Authors: Foster Brian C. , Litster Dionne L. , Buttar Harpal S. , Dawson Brian , Zamecnik Jiri 
Published: October 2006

AbstractThe urinary elimination of 4‐hydroxyamphetamine (PHA) and a series of homologous 4‐alkoxy‐substituted amphetamines and their metabolites was examined after single and multiple oral administration to pregnant and non‐pregnant mice.The metabolic profile and extent of biotransformation in a series of alkoxy analogues were affected by the size of the alkoxy side chain, multiple dosing and pregnancy. There were increased recoveries of both the substrate and the conjugated derivative of PHA during gestation. The major metabolic routes observed were O‐dealkylation, conjugation, and aliphatic hydroxylation of the propoxy side chain. There was some evidence of oxidative deamination. Pregnancy did not alter the profile of the major metabolites detected by GLC and NMR spectroscopy.
Single‐dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers
Authors: Sandouk P. , d'Yvoire M. Bouvier , Chretien P. , Tillement J. P. , Scherrmann J. M. 
Published: October 2006

AbstractA single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half‐life (t1/2β) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and Cmax, as well as a slightly shorter Tmax, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters Cmax, Tmax, and AUC, suggesting that the Coltramyl® tablets have an adequate in vivo dissolution profile.
Comparative bioavailability of two oral formulations of ketorolac tromethamine: Dolac® and Exodol®
Authors: Flores‐Murrieta Francisco J. , Granados‐Soto Vinicio , Castañeda‐Hernández Gilberto , Herrera Jorge E. , Hong Enrique 
Published: October 2006

AbstractThe bioavailability of ketorolac after administration of two oral formulations containing 10 mg of ketorolac tromethamine, Exodol® and Dolac®, to 12 healthy Mexican volunteers was compared. Subjects received both formulations according to a randomized crossover design and blood samples were drawn at selected times during 24 h. Ketorolac plasma concentrations were determined by HPLC and individual plasma‐concentration‐against‐time curves were constructed. Maximal plasma concentration and AUC0‐24. values were compared by analysis of variance followed by Westlake's confidence interval test. 90% confidence limits ranged from 80 to 125% for Cmax and from 85 to 118% for AUC0‐24. It is concluded that the two assayed formulations are bioequivalent.
Disposition of 14C‐dapoxetine in rats: Complementary experiments with whole‐body autoradiographic and tissue dissection techniques
Authors: Bernstein J. R. , Manzione B. M. , Pohland R. C. , Franklin R. B. 
Published: October 2006

AbstractTissue distribution studies, utilizing whole‐body autoradiography and organ dissection techniques, were conducted in male Fischer 344 rats following the oral administration of 14C‐dapoxetine HCl, a potent serotonin reuptake inhibitor. The preliminary study using whole‐body autoradiography proved invaluable in locating radioactivity in an organ not usually harvested in a tissue distribution study, namely the preputial gland. Selected organs, based on whole‐body autoradiography findings, were dissected from rats and analyzed for radiocarbon content by liquid scintillation counting and for parent drug and N‐dealkylated metabolites by extraction and HPLC analysis. Highest concentrations of radiocarbon were observed in the organs of absorption and elimination (ileum, cecum, stomach, duodenum, liver, colon, and kidney) but notable quantities were observed in the lung and preputial and Harderian glands. Most tissues had returned to background radioactive levels 72 h after dosing but persistent concentrations of radiocarbon were present in the preputial gland and liver one week after the single dose of 14C‐dapoxetine.Analysis by HPLC demonstrated the presence of parent drug and N‐desmethyl metabolite (nor‐dapoxetine) in those organs examined; however, the majority of the radioactivity remained unidentified.
Bioavailability and reversible metabolism of prednisone and prednisolone in man
Authors: Garg Varun , Jusko William J. 
Published: October 2006

AbstractThe pharmacokinetics of prednisone and prednisolone was examined in 12 healthy male subjects to assess the bioavailability and the parameters of reversible metabolism between the two steroids. After an oral prednisone dose of 0.8 mg kg−1 and an intravenous prednisolone dose of 0.66 mg kg−1, the bioavailability was found to be about 62%. The fraction of the dose recovered in the urine as the hydroxylated metabolites of prednisone and prednisolone was lower after the oral prednisone dose, suggesting that poor absorption of prednisone was the main cause of the low bioavailability. There was a high degree of interconversion between prednisone and prednisolone with 76% of the dose being recycled. The formation clearance of prednisolone from prednisone is much greater than the formation clearance of prednisone from prednisolone or the irreversible elimination clearances of the two steroids. The possible dose dependences of bioavailability and interconversion may be important factors in prednisolone therapy.
The effect of multiple doses of ranitidine on the pharmacokinetics and metabolism of diltiazem in dogs
Authors: Yeung Pollen K. F. , Mosher Susan J. , Landriault Hélène 
Published: October 2006

AbstractIn order to determine the potential pharmacokinetic drug interaction between ranitidine and diltiazem (DTZ), each of ten male beagle dogs, age 2·7–4·0 years, weight 13–16 kg, received a single oral dose of sustained release DTZ with and without previous multiple oral doses of ranitidine (150 mg bid for five doses). The dog was selected as the animal model because the pharmacokinetics and metabolism profiles of DTZ are similar to those in humans and because sustained release DTZ capsules can be administered with ease to this species. Following the oral dose of DTZ, blood samples (5 ml each) were obtained via a cephalic vein at 0 (just before dosing), 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 30, 36, and 48 h after the dose. Urine samples were collected for 48 h post dose. Plasma and urine concentrations of DTZ and its major metabolites N‐monodesmethyl DTZ (MA), deacetyl DTZ (M1), and deacetyl N‐monodesmethyl DTZ (M2) were determined by HPLC. Pharmacokinetic parameters were calculated by non‐linear curve fitting, and the effect of ranitidine was evaluated by two‐factor analysis of variance (ANOVA). Pre‐treatment of the animals did not significantly alter the disposition of DTZ (p >0·05). Similar to the results reported in clinical studies, there were large variations in the plasma and urine concentrations of DTZ and its major metabolites among the beagle dogs. The effect of ranitidine on the disposition of DTZ was highly variable.
Kinetic modelling of liposome degradation in serum: Effect of size and concentration of liposomes in vitro
Authors: Harashima Hideyoshi , Ochi Yoshihito , Kiwada Hiroshi 
Published: October 2006

AbstractThe purpose of this study is to propose a new method for quantitative evaluation of liposome degradation in serum. The time course of liposome degradation in rat serum was monitored continuously, using 6(5)‐carboxyfluorescein as an aqueous phase marker. The degradation curves exhibited three characteristic phases: lag time, degradation, and plateau. This curve was described by a kinetic model with three parameters: lag time (τ), first‐order degradation rate constant (k), and maximum degradation (α). The rate and extent of the degradation of liposomes were evaluated separately in terms of k and α, respectively. The effects of size and concentration of liposomes on their degradation kinetics were examined using this method. Both k and α increased with increasing liposomal size. The increased affinity of larger liposomes for complement was suggested to increase both k and α. On the other hand, α decreased with increasing liposomal concentration without altering k. The decreased extent of degradation was considered to result from the depletion of complement components. There was no significant effect of size and concentration of liposomes on τ. Quantitative evaluation of the rate and extent of degradation of liposomes will provide deeper insights into the interaction between liposomes and serum components, and basic information on liposomes as potential drug carriers.