摘要:

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

ISSN:0142-2782    

DOI:10.1002/bdd.2510150502

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractIntestinal absorption of γ‐aminobutyric acid (GABA), as a model compound for γ‐aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of β‐alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests toin vivophysiological conditions, a rat jejunumin situstudy was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They show that the intestinal absorption of the γ‐aminoacid can be apparently described as a specialized transport mechanism which obeys Michaelis‐Menten and first‐order kinetics. Parameter values found wereVm= 13.99 ± 2.37 mM h−1,Km= 3.87 ± 0.63 mM, andka(passive) = 0.362 ± 0.120 h−1. Through the perfusion of 5 mM β‐alanine solutions containing variable concentrations of GABA (from 5 to 50 mM), a partially competitive inhibition of β‐alanine absorption

ISSN:0142-2782    

DOI:10.1002/bdd.2510150503

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractSince previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by β‐alanine and therefore mediated, at least in part, by the β‐aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a γ‐aminoacid model compound, γ‐aminobutyric acid (GABA). A rat jejunumin situstudy was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease as the GABA concentration increases, with a limiting value of 0.65 h−1(±0.01). A partial competitive inhibition or complete competitive inhibition in the presence of a passive component could define the interaction phenomena between the two substances. Kinetic absorption parameters for GABA in the presence and absence of baclofen (Ki= 5.67 ± 1.54,Km= 3.87 ± 0.63) suggest the existence of more than one intestinal carrier system for

ISSN:0142-2782    

DOI:10.1002/bdd.2510150504

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe pharmacokinetic profile of the melanotropic peptide, melanotan‐II (MT‐II), was determined in rats following a 0.3 mg kg−1intravenous 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, MRTVdβ, andVss. Statistical comparison showed that the parameters measured by each method were not significantly different (at the 0.05 level) except fort1/2β, MRT andVss. The presence of even one aberrant data point in the β‐phase can significantly influencet1/2βwhen only a few data points are available in the β‐phase. Since MRT andVsswere calculated fromt1/2βit is not surprising that these two parameters also differ

ISSN:0142-2782    

DOI:10.1002/bdd.2510150505

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) injection of free MTX (treatment I), MTX‐loaded proliposomes (treatment II), and empty proliposomes mixed manually with free MTX (treatment III), 8 mg kg−1, to rats using an HPLC assay. After i.v. infusion in 1 min, the plasma concentration of MTX (Cp), the area under the plasma concentration‐time curve (AUC, 639 versus 913 μg min mL−1), the terminal half‐life (t1/2, 48.8 versus 397 min), the mean residence time (MRT, 8.40 versus 325 min), and the apparent volume of distribution at steady state (Vss, 98.1 versus 2800 mL kg−1) were significantly higher; however, the total body clearance (CL, 12.5 versus 8.76 mL min−1kg−1), renal clearance (CLR, 4.49 versus 2.78 mL min−1kg−1), non‐renal clearance (CLNR, 7.50 versus 5.99 mL min−1kg−1), and the amount of MTX excreted in urine (Xu, 808 versus 685 μg,p<0.0948) were significantly lower from treatment II than from treatment I. This could be due to the fact that some of the MTX‐loaded liposomes (formed immediately after hydration of MTX‐loaded proliposomes) are entrapped in tissues and the rest are present in the plasma (higher MRT andVssfrom treatment II), and MTX is slowly released from MTX‐loaded liposomes (highert1/2from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX loaded in liposomes (higherCpand AUC, slower CL from treatment II). After i.v. infusion in 1 min, some pharmacokinetic parameters, such ast1/2, MRT, andVss, were significantly different between treatments I and III; however, the differences seemed to be smaller than those between treatments I and II. After 30 min from i.v. infusion, the tissue to plasma (T/P) ratios of MTX in kidney and stomach from treatment II were significantly lower than those from treatment I. This suggested that the i.v. administration of MTX‐loaded proliposomes might have fewer side effects in the organs than that of free MTX. The mean amount of MTX loaded in MTX‐loaded proliposomes was 2.54 mg/g proliposomes and the MTX was released slowly from hydrated MTX‐loaded proliposomes when incubated with phosphate‐buffered saline (

ISSN:0142-2782    

DOI:10.1002/bdd.2510150506

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

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 mg14C‐MK‐679. Results of this study indicate t

ISSN:0142-2782    

DOI:10.1002/bdd.2510150507

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

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 each14C‐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

ISSN:0142-2782    

DOI:10.1002/bdd.2510150508

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractBenidipine hydrochloride is a calcium antagonist with a 1,4‐dihydropyridine derivative structure, and exhibits long‐lasting antihypertensive effects by inhibiting the voltagedependent Ca2+channels. This study was undertaken to examine the effect of benidipine on central haemodynamics and regional blood flow (RBF) after intravenous administration of benidipine in conscious, spontaneously hypertensive rats. The microsphere method was used to measure cardiac output and RBF before and after the drug administration, using microspheres labelled with57Co and51Cr. Thirty minutes after the intravenous administration of benidipine (3 μg kg−1), the mean arterial pressure fell by 15% without significantly increasing the heart rate. The cardiac output increased by 41% and the systemic resistance decreased by 39%. Benidipine significantly increased RBF by 37,35, and 22% in kidney, heart, and small intestine, respectively, and decreased vascular resistance by 38, 38, and 32%, respectively. We concluded that benidipine reduced blood pressure by increasing RBF in the kidney and heart, while keeping RBF in other organs at a normal level. These results will provide a fundamental basis in support of the clinical benefits of benidipine for hypertensive patients, particularly those with renal f

ISSN:0142-2782    

DOI:10.1002/bdd.2510150509

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510150510

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510150501

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY