bluuebunny/crossref_metadata_2025 huggingface dataset:
Human dolasetron pharmacokinetics: II Absorption and disposition following single‐dose oral administration to normal male subjects
Authors: Boxenbaum Harold , Gillespie Todd , Heck Kathleen , Hahne William
Published: October 2006

Dolasetron is a 5‐hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapyinduced nausea and vomiting. A previous study demonstrated that following intravenous administration to healthy male subjects, dolasetron disappeared extremely rapidly from plasma, and less than 1 per cent of the dose appeared in the urine. A major plasma metabolite, reduced dolasetron, peaked rapidly in the plasma. In this study, dolasetron was administered orally to healthy male subjects at doses ranging from 50 to 400 mg (mesylate monohydrate). Plasma concentrations of dolasetron were low and sporadic, and there was little excreted in urine; this prevented dolasetron pharmacokinetic analysis. Reduced metabolite concentrations peaked rapidly, with a median value of 1.00 h. The median terminal disposition half‐life was 7.80 h. Median values for fraction of dose excreted in urine and renal clearance were 22.2 per cent and 2.56 ml min−1 kg−1. Whereas areas under the plasma concentration—time curves were proportional to dose, renal clearance increased with dose (p < 0.05). However, given dose proportionality to AUC, this is probably of little therapeutic consequence. Since reduced dolasetron has significant anti‐emetic activity in the ferret model, it appears that this metabolite may play a significant role in pharmacodynamic activity.
Pharmacokinetics of D‐propranolol following oral, intra‐arterial and intraportal administration: Contrasting effects of oral glucose pretreatment
Authors: Chow Hsiao‐Hui , Lalka David
Published: October 2006

Several research groups have reported that in man the oral administration of propranolol with food leads to a marked increase (about 50 per cent) in the area under the plasma concentration—time curve (AUCpo) of this well absorbed and highly metabolized drug. An acute change in hepatic metabolic enzyme activity has been postulated as one of the mechanisms which could be responsible for this observed ‘food effect’. The administration of simple carbohydrates such as glucose and fructose has been documented to influence hepatic drug metabolism. Therefore, in the present study, the effect of oral glucose (4 g kg−1 as a 50 per cent aqueous solution) on the disposition kinetics of d‐propranolol was examined in male Sprague‐Dawley rats (8 to 9 per group).

Oral glucose treatment caused a statistically significant decrease (504 ± 12.3 vs 36.6 ± 15.2 min μg ml−1; p < 0.05) in the AUCpo of propranolol when this drug was given by oral intubation (10 mg kg−1). This glucose treatment also caused the apparent mean residence time of propranolol after an oral dose to increase from 0.70 ± 0.08 h to 1.79 ± 0.29 h (p < 0.05), but did not change its rate of elimination (suggesting collectively a decreased apparent intrinsic clearance and prolonged drug absorption). In a second study, the same oral glucose treatment was demonstrated to have little impact on the steady state concentrations of propranolol when this drug was infused intraarterially at a constant rate. This confirms that the systemic clearance of propranolol is influenced minimally by the glucose treatment. In a third study, propranolol was infused at a constant rate into the portal vein (pyloric vein infusion) bypassing the processes of intestinal metabolism and absorption (i.e. to remove these sources of variability associated with oral administration). Under these conditions, no significant changes in AUC or apparent mean residence time were observed for the two propranolol doses studied (10 mg kg−1 and 5 mg kg−1). We conclude that the oral glucose and oral propranolol interaction appears to be due to an alteration in the input process before drug enters the liver. Furthermore, this experimental series suggests that studies combining accurate assessments of systemic clearance (constant rate intra‐arterial infusion studies), intrnsic hepatc clearance (pyloric en infusion studies), ad oral administration supplemented wth necessary protein binding studies may be used together to charenterize te mechanism responsible for drug‐nutrient and drug‐drug interactions.
Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of bumetanide
Authors: Ryoo Si H. , Lee Myung G. , Lee Min H.
Published: October 2006

The pharmacokinetics and pharmacodynamics of bumetanide were evaluated after intravenous (i.v.) administration of the same total dose of bumetanide in different lengths of infusion times, 10 s (treatment I), 1 h (treatment II), and 4 h (treatment III) to rabbits. The fluid loss in urine was immediately replaced volume for volume with i.v. infusion of lactated Ringer's solution. Some pharmacokinetic parameters of bumetanide were infusion time‐dependent and it might be due to the saturable metabolism of bumetanide. For example, the mean values of CL (13.6, 25.3 vs 18.2 ml min−1 kg−1), MRT (9.70, 10.6 vs 21.8 min), Vss (128, 217 vs 378 ml kg−1), and CLNR (2.71, 9.24 vs 6.44 ml min−1 kg−1) increased when the same dose of bumetanide was infused in 1 h or 4 h. However, the mean values of t1/2, and CLR were not significantly different among three treatments. The diuretic effects (urine outputs and urinary excretions of sodium and chloride) increased significantly in 1 and 4 h of infusion although the total amounts of urinary excretion of unchanged bumetanide were 21.8 and 20.5 per cent lower in treatments II and III, respectively, when compared with the value in treatment I; the mean values of 8‐h urine outputs were 373, 922, and 1030 ml for 10s, 1 h, and 4 h of infusion, respectively, and the corresponding values for 24‐h sodium excretions were 49.0, 82.8, and 121 mmol, and for chloride were 47.5, 71.1, and 114 mmol. It could be due to the higher diuretic efficiencies in treatments II and III. Plasma concentrations of bumetanide, and hourly urine outputs and hourly urinary excretion rates of bumetanide, sodium, potassium, and chloride during the apparent steady state (between 1 and 4 h) in the 4 h infusion study were fairly constant.
Bioavailability of metformin in tablet form using a new high pressure liquid chromatography assay method
Authors: Caillé Gilles , Lacasse Yves , Raymond Manon , Landriault Hélène , Perrotta Maria , Picirilli Gianfranca , Thiffault Jean , Spénard Jean
Published: October 2006

Twenty‐four young healthy volunteers received a single dose of metformin 500 mg (Glucophage®, Nordic Laboratories, Canada) in tablet form. Plasma concentrations were determined by HPLC in samples collected prior to and 0.33, 0.66, 1.33, 1.66, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 15, 18, 24, and 30 h after dosing. Mean (± SD) Cmax was 682.1 (160.6) ng ml−1 at a mean (± SD) tmax of 2.4 (0.93) h. Overall elimination was monoexponential with a mean (± SD) half‐life of 3.16 (0.47) h. We conclude that metformin is rapidly absorbed from this formulation and is also rapidly eliminated. Extrapolation to steady state predicts that equilibrium will be reached within 24 h.
Kinetic modeling of liposome degradation in blood circulation
Authors: Harashima Hideyoshi , Kume Yoshihiro , Yamane Chizu , Kiwada Hiroshi
Published: October 2006

The aim of this study is to develop a kinetic model for the quantitative evaluation of, and to examine dose dependency in liposome degradation in blood circulation in vivo. Multilamellar liposomes labeled with 3H‐inulin were administered intravenously into rats and the time courses of blood concentration and urinary excretion of 3H‐inulin were measured. The dosages of liposomes were fixed at 1, 5, and 100 μmolPCkg−1. Remarkable saturation was found in the time courses of both blood concentration and urinary excretion. Then a kinetic model for the degradation of liposomes in blood was developed, assuming that the degradation follows the first order rate process for each dose. The model fitted the observed time courses of excreted 3H‐inulin well, and dose dependency could be observed in the rate constants for liposome degradation, which are more sensitive than urinary excretion of 3H‐inulin. The degradation rate constant correlated well with the uptake rate constant, which suggests the same underlying mechanism for both uptake and degradation. These results indicate the usefulness of kinetic modeling in the quantitative evaluation of liposome degradation in blood circulation in vivo.
Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1‐methyl‐1‐cyclohexanecarboxylic acid
Authors: Liu Mei‐Jen , Pollack Gary M.
Published: October 2006

The pharmacokinetics of valproic acid (VPA) and three structural analogs, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1‐methyl‐1‐cyclohexanecarboxylic acid (MCCA), were examined in female Sprague‐Dawley rats. All four carboxylic acids evidenced dose‐dependent disposition. A dose‐related decrease in total body clearance was observed for each test compound, suggesting the presence of saturable elimination processes. Furthermore, the apparent volume of distribution for these compounds was, with the exception of CCA, dose‐dependent, indicating that binding to proteins in serum and/or tissues may be saturable. Both VPA and MCCA exhibited enterohepatic recirculation, although the degree of recirculation appeared to be dose‐ and compound‐dependent. Significant quantities of both VPA and MCCA were excreted in the urine as base‐labile conjugates, presumably representing glucuronides. In contrast, OA and CCA were not excreted in the urine as base‐labile conjugates and did not evidence enterohepatic recirculation. CCA displayed apparent Michaelis‐Menten kinetics, although the calculated Km was dose‐dependent. The results suggest that relatively minor changes in chemical structure have a marked influence on the metabolism and disposition of low molecular weight carboxylic acids.
Bioequivalence study of nalidixic acid tablets: In vitro–in vivo correlation
Authors: Jung H. , Gonzalez H. , Rodriguez J. M.
Published: October 2006

The USP dissolution test was used to select seven products with a wide range of dissolution characteristics for in vivo examination. The bioequivalence of seven (500 mg) products was evaluated in two crossover urinary excretion experiments. In each study three products were compared with the innovator product (Negram‐Winthrop‐Breon) in 12 subjects according to a 4 × 4 latin square design. Significantly different, lower bioavailability was observed in two products in relation to that of the innovator product. Linear in vitro–in vivo correlations were found between the cumulative amount excreted at 24 h and the log of the amount dissolved at 30 min and between log of the cumulative amount excreted up to 24 h and the log of the amount dissolved at 45 min.
Effect of infusion duration on valproate pharmacokinetics
Authors: Hussein Ziad , Patterson Karen J. , Lamm Janet E. , Cavanaugh John H. , Granneman G. Richard
Published: October 2006

The pharmacokinetics of intravenously administered valproic acid (VPA) were investigated in 16 healthy male volunteers in a single‐dose, fasting, four‐period, randomized, double‐blind, placebo‐controlled, parallel design study. Subjects were randomly assigned to be infused a single dose of sodium valproate equivalent to 1000 mg VPA or placebo over each of four different time periods. Valproate concentrations in plasma were determined using gas chromatography with flame ionization detection. The pharmacokinetic parameters were determined by both non‐compartmental and model‐dependent techniques. Analyses of variance (ANOVAs) were performed to detect any statistical differences among the regimens. Overall, the pharmacokinetics of valproate were similar after infusions of 5, 10, 30, and 60 min, with an average terminal‐phase half‐life of 15.9 h. There were modest differences in overall clearances among the regimens, with the 5 min infusion producing a mean area under the plasma concentration‐time curve (AUC; 1877 μg·h ml−1) that was significantly (13 to 16 per cent) higher than the means for the longer infusions (1614–1656 μg·h ml−1). Differences in distribution were also noted as a function of infusion duration. The shortest duration produced a significantly smaller terminal volume of distribution (12.8 vs 14.2–15.1 l) and more rapid tissue equilibration. The α‐phase rate constant declined from a mean of 5.1 h−1 after the 5 min infusion to a mean of 0.9 h−1 after the 60 min infusion. The distributional differences are almost certainly related to the saturable protein binding of valproate. However, the lower clearance after the 5 min infusion indicates that there may have also been partial saturation of one of the metabolic pathways of valproate during the distributive phase, and that the increase in fu was smaller than the decrease in CL′int, such that the product of fu·CL′int showed a net decrease.
Relationship between lung tissue and blood plasma concentrations of inhaled budesonide
Authors: Van Den Bosch J. M. M. , Westermann C. J. J. , Aumann J. , Edsbácker S. , Tönnesson M. , Selroos O.
Published: October 2006

In 11 patients, in whom a lung lobe or whole lung was to be resected, a single dose of 1.6 mg inhaled budesonide was given pre‐operatively. In 9 of them, concentrations of the drug in both lung tissue and blood plasma were measured. Budesonide concentrations in lung tissue, at least 90 min after dosage, were 2.1–8.9 nmol kg−1. Concentrations in blood plasma (0.27–1.1 nmol kg−1) were 1/8th of those in lung tissue.
Effects of water deprivation on the pharmacokinetics and pharmacodynamics of bumetanide in rats
Authors: Huang Ji Y. , Kim Ok N. , Lee Sun H. , Lee Myung G.
Published: October 2006

The effects of temporary water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of bumetanide were examined after intravenous (i.v.) administration of bumetanide, 8 mg kg−1 to control and water deprived rats (n = 7). The values of AUC, t1/2 and MRT increased 79.0, 417, and 633 per cent, respectively, and CL and CLNR decreased 44.0 and 41.2 per cent, respectively, in water deprived rats. They were all significantly different. The decreased CLNR in water deprived rats could be due to decreased nonrenal metabolism of bumetanide; it could be supported that the amounts of glucuronide conjugate of bumetanide (52.5 vs 12.9 μg), desbutylbumetanide (170 vs 113 μg) and its glucuronide conjugation (191 vs 125 μg), and sum of the three metabolites (414 vs 229 μg), which are expressed in terms of bumetanide excreted in 24 h urine, decreased significantly in water deprived rats. The 8‐h urine outputs per 100 g body weight (4.32 vs 1.34 ml) also reduced significantly in water deprived rats, and it might be due to significantly reduced amounts of bumetanide excreted in 8 h urine (90.9 vs 25.7 μg) and/or reduced kidney function in water deprived rats. The kidney function based on CLlot (9.87 vs 2.14 ml min−1 kg−1) reduced significantly in water deprived rats. The 8‐h urinary excretions of sodium (0.430 vs 0.0818 mmol), potassium (0.567 vs 0.270 mmol), and chloride (0.549 vs 0.0624 mmol) per 100 g body weight also reduced significantly in water deprived rats.
Disposition of enantiomers of sulpiride in humans and rats
Authors: Kamizono Ayako , Inotsume Nobuo , Fukushima Shoji , Nakano Masahiro , Okamoto Yoshio
Published: October 2006

Pharmacokinetics of sulpiride enantiomers after intravenous administration of (±)‐, (+)‐, and (−)‐sulpiride was examined in humans and rats. Pharmacokinetic profiles were similar in (+)‐ and (−)‐enantiomers after intravenous administration of (±)‐sulpiride. Metabolic inversion at a chiral centre was not observed after intravenous administration of each enantiomer in rats.
Relationship between content of hepatic glutathione S‐transferases and the kinetics of indocyanine green elimination in various liver diseases
Authors: Sugimoto Motonobu , Shimada Nagaki , Aikawa Katsunori , Sugiyama Yuichi
Published: October 2006

The glutathione (GSH) S‐transferases are believed to have dual functions as hepatic detoxifying enzymes and intrahepatic binding proteins. Little is known about their alterations in human liver diseases. Therefore, we have studied the relationship between the enzyme activity and rose bengal (RB) binding in hepatic cytosol and plasma indocyanine green (ICG) kinetics in patients with various liver diseases. The enzyme activity was measured in samples of hepatic cytosol obtained from 52 patients. In addition, the content of cationic and neutral transferases was estimated in 17 biopsy samples by densitometry of Coomassie blue stained sodium dodecyl sulphate polyacrylamide gel electrophoretograms. RB binding studies also were performed on cytosol samples. ICG kinetic parameters were determined using the two‐compartment open model in 17 patients who were given the dye (0.5 mg kg−1) intravenously. Correlations between the enzyme activity and liver function tests, content of the enzyme, RB binding and ICG kinetic parameters were evaluated. The following results were obtained. (1) The enzyme activities were high in alcoholic liver disease, fatty liver and Gilbert's syndrome, and low in cirrhosis. (2) The enzyme activities were positively correlated with serum cholinesterase activity, serum albumin level and hepaplastin test, and negatively correlated with ICG retention rate at 15 min. (3) The enzyme activity, its content and RB binding affinity of the cytosol were positively correlated with each other. (4) The enzyme activity was positively correlated with hepatic ICG distribution volume. These results are consistent with the role of the GSH S‐transferases as ligandins in intracellular storage of dyes.
Pharmacokinetic profiles of glycyrrhizin in patients with chronic hepatitis
Authors: Tanaka Naomi , Yamamura Yoshikazu , Santa Tomofumi , Kotaki Hajime , Uchino Katsuyoshi , Sawada Yasufumi , Aikawa Tatsuya , Osuga Toshiaki , Iga Tatsuji
Published: October 2006

The pharmacokinetics of glycyrrhizin (G) in eight patients with chronic hepatitis receiving chronically i.v. administration of 120 mg dose of G was investigated. The plasma concentration of G in the patients after dosing declined in a monophasic manner. However, the pharmacokinetic profiles varied among patients. The mean elimination half‐life (t1/2) and the total body clearance (CLtot) were 6.0 h (range 4.3–10.7 h) and 7.9 ml h−1 kg−1 (4.5–12.7 ml h−1 kg−1), respectively. The variation of the CLtot for G was closely related to that of aspartate aminotransferase (r = −0.739, p <0.05) and alanine aminotransferase (r = −0.783, p <0.05) activities in the plasma.
Cyclosporin A and erythromycin: A study of a drug interaction in the in situ perfused rat liver model
Authors: Hughes C. M. , Swanton J. G. , Collier P. S.
Published: October 2006

Using the in situ perfused rat liver model, the effect of erythromycin (Ery) on the disposition of cyclosporin A (CyA) and the major human metabolite, AMl, was investigated. Prior to perfusion experiments, oral dosing was carried out for three days on three groups of male Sprague—Dawley rats (300–350 g), involving pretreatment with water (control and H2O/Ery groups) or erythromycin (Ery oral group). On the fourth day, perfusion experiments took place using standard techniques, with the addition of 20 mg Ery to the H2O/Ery and Ery oral groups, and 2.5 mg CyA to all groups. Perfusate and bile samples were collected and assayed for CyA and AMl by HPLC. Results indicated that inhibition of CyA metabolism had occurred as the CyA concentration in perfusate was significantly higher in both Ery groups at all times compared to the control group, and the levels of AMl in both perfusate and bile were significantly lower than in the control group. There was also a marked reduction in the apparent metabolic clearance of CyA in the Ery groups. It was concluded that AMl production had been inhibited by Ery, the most likely mechanism being inhibition of the isoenzyme CYP3A with which Ery forms a stable complex.
Distribution characteristics of immunosuppressants FK506 and cyclosporin A in the blood compartment
Authors: Takada Kanji , Katayama Naohisa , Kiriyama Akiko , Usuda Hisato
Published: October 2006

Using two representative immunosuppressants, FK506 (FK) and cyclosporin A (CyA), of which the mechanism of pharmacological action is the same although there is a great difference in the pharmacological intensity, the distribution characteristics were studied in both in vivo and in vitro experiments using rat, dog, and human blood. Blood samples were fractionated by means of sedimentation in Ficoll‐Paque®, and the drug contents in the diluted plasma fraction, erythrocyte fraction, and lymphocyte fraction were measured by an HPLC method. FK distributes to the lymphocyte fraction to a level about three times greater than that of CyA, while CyA distributes to the erythrocyte fraction to a level ten times that of FK. The distribution pattern of these fractions was independent of the drug concentration and species after correcting the drug concentration in each fraction with the blood drug concentration. The uptakes of FK and CyA in the isolated lymphocytes obtained from the rat spleen and human peripheral blood were also studied. The amount of FK taken up by the spleen lymphocytes is five times greater than that of CyA. In the case of the uptake study using human peripheral blood lymphocytes, the concentration of FK in the lymphocyte is 100‐fold higher than that of CyA. This difference in the lymphocyte level between the two immunosuppressants is thought to be one of the reasons why FK is more potent than CyA, a difference of about 100‐fold in the in vitro pharmacological study and about tenfold in the in vivo organ transplantation experiments.
Pharmacokinetics of anticholinergic drugs and brain muscarinic receptor alterations in streptozotocin diabetic rats
Authors: Nakashima Emi , Ishizaki Junko , Takeda Masami , Matsushita Ryo , Yokogawa Koichi , Ichimura Fujio
Published: October 2006

We studied the effects of experimental diabetes on the pharmacokinetics of biperiden (BP) and scopolamine (SP) and brain muscarinic receptor alterations in rats after the injection of streptozotocin (STZ) (60mg kg−1 i.v.). The serum levels of BP and SP differed significantly between the rats 14 weeks after the STZ treatment and age‐matched control rats. The values of total body clearance (CLtot) of BP and SP were significantly increased by STZ treatment. The values of volume of distribution (Vdss) of SP were slightly increased in the STZ‐treated rats, although Vdss of BP was decreased. Because of the high lipophilicity of BP, Vdss of BP may be decreased due to the reduced fat tissue volume caused by STZ treatment.

The density of the muscarinic receptors in whole brain was measured by a radioligand receptor binding assay using [3H]‐quinuclidinyl‐benzylate ([3H]‐QNB). The density in the diabetic rats two weeks after the STZ treatment was significantly decreased compared to age‐matched control rats. However in the diabetic rats 14 weeks after the STZ treatment, there was no difference in the density of muscarinic receptors. The IC50 of muscarinic antagonist for the binding of [3H]‐QNB to the receptor did not change on STZ treatment. Modulation of the receptor following repeated anticholinergic drug exposure was studied. In control rats, the number of muscarinic receptors in the brain increased by 6.9% on chronic treatment with BP for two weeks. When diabetic rats were treated with BP and SP, the number of muscarinic receptors in the brain increased by 9.6% and 33.8%, respectively.
Dose‐dependent pharmacokinetics: Experimental observations and theoretical considerations
Authors: Lin Jiunn H.
Published: October 2006

Clinically, absorption and elimination of most drugs follow linear kinetics, and pharmacokinetic parameters describing absorption and elimination of a drug do not change over the therapeutic dose range. However, dose‐dependent pharmacokinetics have been reported more frequently in preclinical studies, particularly in toxicity studies, where high doses are often employed. This review highlights the major types of dose‐dependent pharmacokinetics with unique examples.

Before setting out on a pivotal subchronic and chronic toxicity study of a new drug, a pilot study is often performed to establish a dose range in which a reasonable relationship between plasma AUC and dosage exists to ensure sufficient exposure of animals to the drug. Theoretical bases and possible causes of dose‐AUC disproportionality are discussed.

Factors affecting the distribution and elimination of drugs and causes of dose‐dependent tissue distribution and elimination are also discussed. Often, the non‐linear kinetics complicate the design of dosage regimens and prediction of efficacy and toxicity. Thus, an understanding of the influence of dose on the pharmacokinetics is important in the evaluation of the efficacy and toxicity of new drugs.
Pharmacokinetic analysis of two new sustained‐release products of diltiazem designed for twice‐and once‐daily treatment
Authors: Bialer Meir , Hadad Salim , Golomb Gershon , Barel Shimon , Samara Emil , Salach Omar Abu , Berkman Nevil , Danenberg Haim D. , David Joseph Ben , Caron David , Kaplan Roman , Tamir Arnon , Friedman Michael
Published: October 2006

The pharmacokinetics of two new sustained‐release (SR) products of diltiazem, Dilapress 120 mg tablets and Dilapress 240 mg tablets, was analysed and characterized in three different studies, in comparison to the following diltiazem SR formulations: Cardizem Retard, Cardizem SR, and Cardizem CD. Dilapress 120, designated for twice‐daily dosing, was found to be bioequivalent to Cardizem SR and to Cardizem Retard with mean (±SD) relative bioavailability values of 99 ± 27% and 113 ± 38%, respectively. Dilapress 240, designed for once‐a‐day treatment, was found to have a slower absorption rate than Cardizem SR and its extent of absorption was 56 ± 19% relative to that of Cardizem SR. However, the bioavailability of Dilapress 240 relative to that of Cardizem CD was 118±46%, indicating that the bioavailability of Cardizem CD relative to that of Cardizem SR was only 54±29%. Diltiazem is partially available due to a saturable liver first‐pass effect. A high dose of Cardizem SR may partially escape this first‐pass effect and, thus, achieve a higher extent of absorption than a slower SR product. Consequently, SR products of diltiazem designed for once‐daily treatment may not reach the saturation stage in the liver first‐pass effect process that diltiazem is susceptible to. Consequently, a twice‐daily SR product of diltiazem cannot serve as a reference for extent of absorption assessments of a once‐daily SR product.
Pharmacokinetics and bioavailability of oral ergometrine in male volunteers
Authors: De Groot A. N. J. A. , Vree T. B. , Hekster Y. A. , Van Den Biggelaar‐Martea M. , Van Dongen P. W. J. , Van Roosmalen J.
Published: October 2006

The aim of this investigation was to assess the pharmacokinetics and bioavailability of ergometrine in six human male subjects after an oral dose of 0·200 mg and after an intravenous dose of 0·075 mg of ergometrine maleate. A large variation in bioavailability of between 34% and 117% in the six volunteers was observed. The lag time was also subject dependent and ranged between 0·0073 h (0.4 mm) and 0·47 h (28 min). After intravenous administration, the pharmacokinetic profile can be described by a twocompartment model. The distribution half‐life t1/2α is 0·18 ± 0·20 h, the elimination half‐life t1/2β is 2·0 ± 0·90 h, the total body clearance (CL) amounts to 35·9 ± 13·41 h−1 and the steady‐state volume (Vss) of distribution is 73·4 ± 22·01. After oral administration, the pharmacokinetic profile can be described by a one‐compartment model. The absorption half‐life t1/2abs is 0·19 ± 0·22 h, and the elimination half‐life t1/2β 1·90 ± 0·16 h. This study with oral ergometrine shows such a large interindividual variability in bioavailability that the oral route of administration does not seem not to be the most reliable means of accurate dosing in preventing post‐partum haemorrhage.
Dose dependent absorption and linear disposition of cyclosporin A in rat
Authors: Lindberg‐Freijs A. , Karlsson M. O.
Published: October 2006

The pharmacokinetics of cyclosporin A (CyA) were investigated in the rat following intravenous doses of 1·7, 3·3, and 6·4 mg kg−1 and oral doses of 3·1, 6·8, and 12·9 mg kg−1. The blood concentration‐time profile after intravenous administration was adequately described by a two‐compartment model when all data were simultaneously analysed using NONMEM. The disposition pharmacokinetics were linear over the dose range studied; the average total blood clearance was 0·191 g−1 kg−1. The absorption process could not be adequately described by either a first‐ or a zero‐order input. Therefore, a flexible, staircase input model was used and found to be superior to the standard models. The shape of this model was biphasic, with a higher initial input rate than expected from first‐order absorption. The duration of this first phase increased with dose. The extent of absorption was also dose dependent. Bioavailability was higher at higher doses; the values were 45%, 67% and 76% for the three ascending dose levels. These results strongly indicate a saturable first‐pass effect. Since the extraction of CyA in the liver is only 6%, the marked increase in bioavailability of CyA is most likely to be the result of saturated gut wall metabolism.
Contribution of serum lipoproteins as carriers of antitumour agent RS‐1541 (palmitoyl rhizoxin) in mice
Authors: Tokui T. , Kuroiwa C. , Tokui Y. , Sasagawa K. , Kawai K. , Kobayashi T. , Ikeda T. , Komai T.
Published: October 2006

The tumour uptake as well as the anti‐tumour activity of RS‐1541 (palmitoyl rhizoxin), a potent antineoplastic agent, were investigated in mice bearing M5076 sarcoma. After intravenous administration, 14C‐RS‐1541 preferentially bound to the lipoproteins, to which 14C‐rhizoxin did not bind. 14C‐RS‐1541 showed persisting high concentrations of radioactivity in the plasma (T1/2α, 4·9 h). The uptake of radioactivity by the tumour was second to those by the liver and spleen, and several times greater than those by the other tissues. Selective and sustained uptake by the tumour was also demonstrated by wholebody autoradiography. A considerable amount of rhizoxin was detected only in the tumour after administration of 14C‐RS‐1541, and the area under the tissue‐concentration‐time curve (AUCt) and the mean residence time (MRT) of rhizoxin in the tumour were much higher than those after administration of 14C‐rhizoxin itself. The rhizoxin formation in the tumour was significantly reduced by chloroquine, a lysosomal enzyme inhibitor. RS‐1541 showed a higher therapeutic activity than rhizoxin. At a 4 mg kg−1 dose, the maximum growth inhibition was 92% for RS‐1541 and 41% for rhizoxin. These results indicate that RS‐1541, but not rhizoxin, is taken up by the tumour via endocytosis, most likely via the low‐density‐lipoprotein receptor, after binding to lipoproteins. Thus, RS‐1541 was considered to exhibit sustained high concentration in tumours and potent anti‐tumour activity.
Pharmacokinetics of aditoprim and trimethoprim in buffalo calves
Authors: Iqbal M. Perwaiz , Ashfaq M. Khalid , Niazi Sarfaraz K. , Mahboobali M. , Khawaja Khalid N.
Published: October 2006

Pharmacokinetic parameters of two antifolates, trimethoprim and aditoprim, were studied in buffalo calves. The elimination half‐life of aditoprim (6.14 h) was nearly twice as long as that of trimethoprim (3.08 h) and compares well with values observed in heifers. This longer half‐life of aditoprim is a result of its much larger distribution volume (four to five times larger) because the clearance of aditoprim was about twice as high as that of trimethoprim. The longer half‐life of aditoprim is expected to give a longer duration of in vivo bacteriostatic activity than that of trimethoprim.
Pharmacokinetics and pharmacodynamics of a slow‐release formulation of diltiazem after the administration of a single and repeated doses to healthy volunteers
Authors: Lefebvre M. , Lacasse Y. , Spénard J. , Geadah D. , Moisan R. , Gossard D. , Landriault H. , Du Souich P. , Caillé C.
Published: October 2006

Diltiazem is a calcium antagonist used in angina pectoris and hypertension. There is little information concerning the slow‐release (SR) formulation in the literature. The pharmacokinetics of diltiazem SR (120 mg) have been assessed over a 36 h period in healthy volunteers after single‐ (SD) and multiple‐dose (MD) administrations. Cmax, AUC0–36, and AUC0–∞ were significantly increased at steady state compared to the extrapolated SD values, suggesting accumulation of the drug.

Renal and cardiovascular parameters have also been assessed at intervals of 3–6 h during baseline (B) and following single and multiple doses of diltiazem SR. Diuresis over a 24 h period was increased, but not significantly, by the administration of diltiazem SR i.e. 1782 ml (MD) and 1915 ml (SD), versus 1626 ml (B). Natriuresis and creatinine clearance were slightly decreased by diltiazem SR, compared to B values; this might be due to the relatively short period over which steady state was maintained (five days) and the effects of norepinephrine and angiotensine II on renal vasculature and the pharmacokinetics of diltiazem SR. No increase in the systolic blood pressure occurred after the administration of diltiazem SR; diastolic blood pressure and PR interval were decreased and increased respectively by diltiazem SR. These results do not appear to be clinically significant.

Finally, no relation was found between the pharmacokinetics and pharmacodynamics of diltiazem. This may be attributed to the absence of clinically significant effects in healthy volunteers, the presence of active metabolites, the pharmacokinetics of the SR formulation and/or the accumulation of the drug at steady state.
The effect of hepatic disease on the disposition of moricizine in humans
Authors: Pieniaszek Henry J. , Davidson Anna F. , McEntegart Carol M. , Quon Check Y. , Sampliner Richard E. , Mayersohn Michael
Published: October 2006

The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine‐2‐carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased Cmax (59%), an increased t1/2 (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for tmax and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half‐lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.
Pharmacokinetics of SDZ 64‐412, a novel antiasthmatic agent, following intravenous, oral, and inhalation dosing in the rat
Authors: Charnick Steven B. , Yu Zhiling , Athill Lawrence V. , Karara Adel H. , Tse Francis L. S. , Lau David T.‐W.
Published: October 2006

The pharmacokinetics of SDZ 64–412, an antiasthmatic agent, were investigated following intravenous, oral, and inhalation dosing in rats. 14C‐SDZ 64–412 was administered intravenously (2.75 mg kg−1) and orally (5.5 mg kg−1, 110 mg kg−1), whereas non‐radiolabeled drug (5.04 mg kg−1) was administered using nose‐only inhalation chambers. Radioactivity and parent drug concentrations in blood, lung, and excreta were determined at designated times post‐dose. SDZ 64–412 was rapidly and extensively (∼80%) absorbed following both oral doses, although absorption appeared to be prolonged with increasing dose. The absorbed drug was shown to undergo extensive and saturable first‐pass metabolism. The bioavailability of the parent drug, calculated by dose‐normalized AUC and deconvolution methods, was only 10–15% from the low dose, but increased to ∼40% following the high dose. Following inhalation dosing, SDZ 64–412 concentrations in blood and lungs increased rapidly, and did not decline immediately after termination of dosing. The inhalation dose yielded a bioavailability of ∼40%, and AUC of the drug in lungs was approximately 25 times greater than in blood. In general, SDZ 64–412 was extensively distributed and rapidly eliminated from the systemic circulation. Biliary excretion was the predominant route of radioactivity excretion. The present findings suggest that inhalation administration provides a viable means of delivery of SDZ 64–412.
Comparative bioavailability of clofazimine coevaporate in the pig
Authors: Krishnan T. R. , Abraham Isaac
Published: October 2006

The systemic availability of a solid dispersion (coevaporate) of clofazimine (CLF) in poly(vinyl methyl ether maleic anhydride) copolymer (PVM/MA) was tested in the pig. Single 100 mg oral doses of the coevaporate and the commercial product, Lamprene® (Ciba‐Geigy) were administered on separate occasions (separated by a two‐week washout period) to four pigs (two males, two females) in a random cross‐over study. Multiple plasma samples, obtained from an indwelling jugular‐vein cannula, following drug administration, were analyzed by an HPLC method for CLF. Pharmacokinetic analyses of the plasma CLF concentration—time data were performed. A paired t‐test indicated significant differences (p<0.05) between the coevaporate and Lamprene® in the Cpmax, tmax, and AUC. The calculated relative systemic bioavailability (Frel) of CLF from the coevaporate, relative to that from Lamprene®, was three. It is concluded that formulation of CLF, as a solid dispersion, may provide enhanced aqueous dissolution and systemic absorption and may also provide high therapeutic blood levels. These could lead to reduction in the current therapeutic doses and, consequently, minimization of drug‐related side effects.
A comparison of HPLC and bioassay methods for plasma melanotan‐II (MT‐II) determination: Application to a pharmacokinetic study in rats
Authors: Ugwu Sydney O. , Blanchard James , Nguyen Linh D. , Hadley Mac E. , Dorr Robert T.
Published: October 2006

The pharmacokinetic profile of the melanotropic peptide, melanotan‐II (MT‐II), was determined in rats following a 0.3 mg kg−1 intravenous dose. Regression analysis of the plasma MT‐II concentrations determined using HPLC and bioassay methods indicated the existence of a significant linear correlation (r = 0.90, p < 0.001). The plasma concentration versus time plots determined using the two assay methods yielded biphasic disposition profiles that were essentially superimposable. The following pharmacokinetic parameters were assessed from plasma concentration versus time data using both methods: Cmax, AUC, CLs, t1/2β, MRT Vdβ, and Vss. Statistical comparison showed that the parameters measured by each method were not significantly different (at the 0.05 level) except for t1/2β, MRT and Vss. The presence of even one aberrant data point in the β‐phase can significantly influence t1/2β when only a few data points are available in the β‐phase. Since MRT and Vss were calculated from t1/2β it is not surprising that these two parameters also differed between methods.
The bioavailability and nonlinear pharmacokinetics of MK‐679 in humans
Authors: Cheng Haiyung , Schwartz Jules I. , Lin Charles , Amin Raju D. , Seibold James R. , Lasseter Kenneth C. , Ebel David L. , Tocco Dominick J. , Rogers J. Douglas
Published: October 2006

MK‐679 (R(−)‐3‐((3‐(2‐(7‐chloro‐2‐quinolinyl)ethenyl)phenyl)(3‐(dimethylamino)‐3‐oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD4‐receptor antagonist. The disposition of MK‐679 was investigated in a three‐way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK‐679. A greater than proportional increase in the area under the plasma concentration—time curve of MK‐679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two‐compartment model with linear tissue distribution and Michaelis‐Menten elimination from the central compartment, indicating that the elimination of MK‐679 in humans is saturable. In a previous study, the disposition of MK‐679 in humans was also dose‐dependent when given together with its S(+)‐isomer, L‐668,018. Thus, the disposition of MK‐679 in humans is dose‐dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK‐679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK‐679 and intravenous infusion of 1 mg 14C‐MK‐679. Results of this study indicate that the oral bioavailability of MK‐679 is nearly quantitative.
The effect of oral dose volume on the absorption of a highly and a poorly water soluble drug in the rat
Authors: Nickerson David F. , Weaver Margaret L. , Tse Francis L. S.
Published: October 2006

The influence of dose volume on drug absorption following oral administration of a highly and a poorly water soluble drug was examined in male Sprague‐Dawley rats. A constant mass of each 14C‐labeled compound was given via gavage in dose volumes of 1, 5, 10, and 20 mL kg−1. Blood levels, as well as the quantitative excretion of radioactivity, were measured following each treatment. No significant changes in either the rate or extent of absorption of the water soluble drug were detected. In contrast, the absorption rate of the poorly water soluble drug increased with higher dose volumes, whereas no changes in the extent of absorption were observed. Drug solubility and gastric emptying appeared to be important factors affecting the rate of absorption of the poorly water soluble drug. Since changes in dose volume may affect the absorption characteristics of orally administered compounds, and the extent of such changes may be dependent upon the physicochemical properties of the drug, it is apparent that dose volume is an important experimental variable to be considered in studies comparing absorption data.
The absence of a pharmacokinetic interaction between aspirin and the angiotensin‐converting enzyme inhibitor benazepril in healthy volunteers
Authors: Sioufi A. , Pommier F. , Gauducheau N. , Godbillon J. , Choi L. , John V.
Published: October 2006

Potential effects of the coadministration of single doses of aspirin (325 mg) and of benazepril hydrochloride (20 mg) on the pharmacokinetics and the metabolism of these two drugs were evaluated in 12 healthy subjects. Plasma concentration profiles of benazepril, its active metabolite benazeprilat, and total salicylic acid were determined together with urinary excretion of benazeprilat, salicylic acid, salicyluric acid, and salicylate glucuronides. Almost superimposable plasma profiles of benazepril, benazeprilat, and total salicylic acid were achieved with the drugs given alone and concomitantly. The coadministration of benazepril hydrochloride and aspirin did not modify the pharmacokinetics or the metabolism of the two drugs.
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

Vigabatrin (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

The 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

Inter‐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.