bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distribution characteristics of immunosuppressants FK506 and cyclosporin A in the blood compartment
Authors: Takada Kanji , Katayama Naohisa , Kiriyama Akiko , Usuda Hisato 
Published: October 2006

AbstractUsing 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

AbstractWe 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

AbstractClinically, 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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractPharmacokinetic 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

AbstractDiltiazem 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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractMK‐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

AbstractThe 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

AbstractPotential 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.