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151.
The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethylnitrosamine
(DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using
the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased
by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr)
of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life (t1/2) in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution
at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL (8.67±4.85%) decreased
about four-folds, but in DMNA (73.00±9.85%) similar result, was observed as compared with the control. Increased free fraction
of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline
was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline
in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results
suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline. 相似文献
152.
A. Le Liboux A. Frydman B. Oosterhuis J. H. G. Jonkman M. Teule 《European journal of clinical pharmacology》1994,47(4):361-366
The indirect effect of diet on the single-and multiple-dose pharmacokinetics of sustained-release ketoprofen was studied in 16 healthy male volunteers. In an open, cross-over design, 200 mg ketoprofen was administered as a gastric-juice-resistant, sustained-release tablet once daily during two periods of 5 days. A low-calorie/low-fat diet (LCFD) was given in the first period and a high-calorie/high-fat diet (HCFD) in the second period. The first meal on each day was given 4 h after drug intake. Ketoprofen plasma concentrations were measured over 24 h after the first dose on day 1 and over 36 h after the final dose on day 5 of each period.On average, plasma concentrations of ketoprofen were higher with the LCFD than with the HCFD. With the HCFD there was a tendency to longer absorption-lag times on day 5. The maximum concentration and the area under the curve over one 24-h dosage period (AUC0–24) were significantly higher with the LCFD, both on day 1 and on day 5. For AUC0–24 the differences were on average 15% (day 1) and 24% (day 5). The same tendency was observed for the amount excreted in urine over 24 h (Ae), but the difference was only significant on day 1 (14%). The elimination rate constant (K) and the mean residence time were similar for the two diets, both on day 1 and on day 5.From these results, we conclude that there was an acute indirect effect of diet when a meal was had 4 h after intake of the medication. This resulted in a greater extent of ketoprofen absorption with the LCFD than with the HCFD. The absorption rate was apparently not influenced by this acute effect. The longer gastric residence time of ketoprofen with the HCFD may be the result of a long-term indirect effect on gastric emptying rate. If the extreme difference between the diets in this study is taken into account, it seems unlikely that the observed indirect effects have implications for clinical practice. 相似文献
153.
F. Combarnous D. Fouque N. Bernard R. Boulieu P. Chossegros M. Laville P. Zech 《European journal of clinical pharmacology》1994,46(4):379-381
The pharmacokinetics of ganciclovir was evaluated in a 73-year old anuric, haemodialyzed patient given 1.25 mg·kg-1 at the end of each haemodialysis session, three times per week.A biexponential decrease in plasma ganciclovir was observed, with a peak concentration of 3.7 mg·1-1 followed by a steady state value of 2.6 mg·1-1 for almost 40 h. The total plasma clearance was 0.05 ml·min-1·kg-1, the volume of distribution at steady state was 0.61·kg-1, the elimination half life was 132 h, the area under curve was 372 g·h·ml-1, the mean residence time was 190 h, and the percentage of ganciclovir cleared from plasma after a 5 h haemodialysis session was 52.1%.The simulated pharmacokinetics over one month, following the same scheme of administration, did not suggest marked accumulation of ganciclovir. These results were obtained after a reduction of 58% in the recommended dose in patients with impaired renal function. 相似文献
154.
C. Volz-Zang B. Eckrich P. Jahn B. Schneidrowski B. Schulte D. Palm 《European journal of clinical pharmacology》1994,46(5):399-404
The effects of esmolol at different rates of infusion (100, 250 and 500 g·kg–1 BW·min–1) were compared with -adrenoceptor occupancy (1 and 2, estimated by a subtype selective radioreceptor assay) and plasma concentrations of esmolol and its acid metabolite were measured by HPLC. Up to a rate of infusion of esmolol of 500 g·kg–1 BW·min–1 there was a maximal 1-receptor occupancy of 84.7% while 2-receptor occupancy was below the detection limit; confirming the 1 selectivity of esmolol. Exercise-induced increases in heart rate and systolic blood pressure were reduced by esmolol in a dose-dependent manner. The estimated EC50 values of rate of infusion for the reduction in heart rate and systolic blood pressure during exercise were 113 and 134 g·kg–1 BW · min–1, respectively. Additionally, heart rate and systolic blood pressure were reduced moderately at rest. Because of the short elimination half-life of esmolol caused by the rapid hydrolysis to its acid metabolite, 45 min after end of infusion high plasma concentrations of the metabolite (maximally 80 g·ml–1) but no esmolol were detectable. Since no in vivo effects have been observed, despite the presence of high plasma concentrations of the metabolite, the metabolite did not participate in the observed effects up to an infusion rate of esmolol of 500 g·kg–1 BW·min–1. The plasma concentrations of antagonist detected by radioreceptor assay and plasma concentrations of esmolol detected by HPLC showed a good correlation (r=0.97). Since the cardiovascular effects, determined before and 45 min after termination of infusion of esmolol were similar, it can be concluded that the observed effects on heart rate and systolic blood pressure are exclusively mediated by esmolol.Dedicated to Dr. P.Rajagopal, Kuantan Specialist Hospital, Kuantan, Malaysia 相似文献
155.
The effects of acute and chronic stages of carrageenan-induced air-pouch inflammation on the pharmacokinetics of prednisolone were studied in male Wistar rats. Chronic inflammation produced a significant increase in the area under the curve (AUC) of prednisolone compared to control animals (6594 ± 2144 vs 3530 ± 2164 µg · hr/ L). The effect of acute inflammation was not significant (AUC = 4996 ± 3813). Both acute and chronic inflammation also reduced thein vitro plasma protein binding of prednisolone, the reduction being much greater after chronic inflammation. The AUC of free prednisolone after chronic inflammation was 3141 µg · hr/L, compared to 1121 µg · hr/L in the control group and 1823 µg · hr/L after acute inflammation. The mean values of half-life and apparent volume of distribution at steady-state in each group were similar. These results indicate that prednisolone must be used with caution in the treatment of inflammatory diseases because of higher free concentrations of the steroid. 相似文献
156.
Masato Kochi Shuichi Takaki Jun -ichi Kuratsu Hiroshi Seto Isao Kitamura Yukitaka Ushio 《Journal of neuro-oncology》1994,19(3):239-244
Summary Ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), a water soluble nitrosourea with log P-0.71, may be efficacious in the treatment of subarachnoid dissemination of malignant glioma. We used 2 dogs to study the neurotoxicity and pharmacokinetics of MCNU. MCNU (1 mg), dissolved in 10 ml of artificial CSF, was administered via the right lateral ventricle during a period of 18 to 42 min and the CSF was drained by lumbar puncture. The perfusion was repeated once a week for 10 consecutive weeks. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord showed local denudation of the ependyma and local subependymal spongy degeneration and gliosis in the lateral ventricle into which MCNU was administered in one dog and local denudation of the ependyma in the other. When administration was over a period of 21 to 38 min, the MCNU concentration in the lumbar CSF peaked at 11.11 to 50.67 g/ml, in 28 to 78 min. The area under the drug concentration-time curve (AUC) was 1152 g×min/ml on average, significantly larger than that of ACNU. The elimination phase followed linear kinetics and the half-time was 41.1 min on average, significantly longer than that of ACNU. These findings suggest that ventriculolumbar perfusion of MCNU may be effective in the treatment of subarachnoid dissemination of malignant glioma notwithstanding some local histological changes. 相似文献
157.
The Use of Intracerebral Microdialysis to Determine Changes in Blood-Brain Barrier Transport Characteristics 总被引:2,自引:0,他引:2
de Lange Elizabeth C. M. Hesselink Mayke B. Danhof Meindert de Boer Albertus G. Breimer Douwe D. 《Pharmaceutical research》1995,12(1):129-133
The aim of this study was to determine whether changes in the transport of drugs into the brain could be determined by in vivo intracerebral microdialysis. Atenolol was used as a model drug to determine blood-brain barrier (BBB) transport characteristics. In rats, unilateral opening of the blood-brain barrier was achieved by infusion of hyperosmolar mannitol (25%, w/v) into the left internal carotid artery. BBB transport, expressed as the ratio of the area under the curve (AUC) of atenolol in brain extracellular fluid over plasma, was three times higher for the mannitol treated hemisphere as compared with the contralateral brain or after infusion of saline, being (mean ± SEM) 0.094 ± 0.024 (n = 16), 0.029 ± 0.007 (n = 12) and 0.030 ± 0.009 (n = 12) respectively. Further evaluation of the data indicated that for experiments performed in the morning the mannitol infusion had little effect on the extent of transport of atenolol into the brain, while in the afternoon BBB transport was about 10-fold higher than in the contralateral and saline group. The mean afternoon ratios ± SEM were 0.155 ± 0.038 (n = 8), 0.012 ± 0.003 (n = 6) and 0.018 ± 0.006 (n = 6) respectively. It is concluded that intracerebral microdialysis is capable of revealing changes in BBB transport and regional and time-dependent differences in drug levels can be demonstrated with the use of this technique. 相似文献
158.
159.
Preclinical pharmacokinetics and antitumor activity of imexon 总被引:2,自引:0,他引:2
Robert T. Dorr James D. Liddil Mary Kay Klein Evan M. Hersh 《Investigational new drugs》1995,13(2):113-116
Summary Imexon is an aziridine compound originally studied for immune-enhancing effects on lymphocytes. The drug was well-tolerated in humans and was shown to be active in a variety of animal tumor models. Recently, imexon has demonstrated antitumor activity in human multiple myeloma cell linesin vitro. The pharmacokinetics of the compound using a normal phase HPLC assay were studied in normal mice and in dogs with mast cell tumors. Doses of 100 mg/kg given intraperitoneally produced peak plasma levels over 100 (ml in mice and the drug was rapidly eliminated with half lives of 8 minutes ( phase) and 29 minutes ( phase). Only 20% of an oral imexon dose was absorbed in the mouse. In dogs, the and phase half lives ranged from 18–26 minutes and 91–110 minutes, respectively. Peak levels over 100 g/ml were obtained following intravenous doses of 12.5 mg/kg and 25 mg/kg. Imexon was active in mice bearing either P-388 or L-1210 leukemia, but not in mice with B-16 melanoma. These results suggest that cytotoxic drug concentrations can be obtainedin vivo and that imexon is active in lymphoproliferative tumors. 相似文献
160.
Wright Jennifer D. Ma Tianwei Chu Chung K. Boudinot F. Douglas 《Pharmaceutical research》1995,12(9):1350-1353
Purpose. The objective of this study was to characterize the pharmacokinetics of 1 -(2-deoxy-2-fluoro--L-arabinofuranosyl)-5-methyluracil (L-FMAU), a nucleoside analogue with potent activity against the hepatitis B virus and the Epstein-Barr virus, in rats.
Methods. Three doses of L-FMAU were administered intravenously (10, 25, and 50 mg/kg) to rats, and L-FMAU concentrations in plasma and urine were measured by HPLC. Pharmacokinetic parameters were generated by using area-moment analysis.
Results. There were no significant differences in the pharmacokinetic parameters between the three doses ( < 0.05). Thus, the disposition of L-FMAU was linear over the dosage of 10 to 50 mg/kg. Plasma concentrations of L-FMAU declined rapidly with a terminal phase half-life of 1.33 ± 0.45 h (mean ± SD). Total clearance of L-FMAU was moderate, averaging 1.15 ± 0.28 L/h/kg. The fraction of compound excreted unchanged in urine was 0.59 ± 0.13. No glucuronide metabolite was found in the urine. The steady-state volume of distribution was 1.12 ± 0.26 L/kg indicating intracellular distribution of the compound. The fraction of L-FMAU bound to plasma proteins was approximately 15% and was independent of nucleoside concentration.
Conclusions. The pharmacokinetics of L-FMAU in rats were independent of dose over the dosage range of 10 to 50 mg/kg. 相似文献