摘要:

AbstractThe pharmacokinetics of alminoprofen in plasma and synovial fluid (SF) at steady state (300 mg t.i.d.) was studied in 45 patients with knee effusion. Plasma and SF samples, one each per patient, were obtained. Six groups were made according to the time of sampling after ingestion of the 13th dose: 1h (n= 7), 2h (n= 7), 4h (n= 7), 6h (n= 10), 8h (n= 6), 12h (n= 8). A three‐compartment model was used to describe alminoprofen kinetics in plasma and SF, with two parameterizations, a ‘classical’ and a ‘physiological’ one. The non‐linear mixed effect model approach was used to estimate the mean and variance of the pharmacokinetic parameters. The mean ±SE of the estimates (coefficient of variation ofinterindividual variability as a percentage) were volume of distribution, 11.0 ± 1.711 (12%); elimination rate constant, 0.236 ± 0.025 h−1(18%); absorption rate constant 2.80 ± 0.31 h−1(464%), clearance of influx into SF, 0.29 ± 0.14 mL min−1; clearance of efflux into plasma, 0.56 ± 0.25 mL min−1. These two clearances were not significantly different, which indicates that passive diffusion occurs in both directions. The mean ±SD alminoprofen concentration versus time curve in plasma and SF at steady state was simulated and showed that the mean ±SD maximal concentration in SF was 8.1 ± 6.3 mg L−1and was obtaine

ISSN:0142-2782    

DOI:10.1002/bdd.2510160803

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractA newly developed autoinjector (Astra Tech, Sweden) containing 500 mg HI‐6 and 2 mg atropine sulphate was tested in anaesthetized normal pigs. The pharmacokinetics and pharmacodynamics of the drugs after administration by the autoinjector were compared with those after conventional needle and syringe delivery intramuscularly and intravenously. Cardiopulmonary parameters were monitored and serum concentrations of oxime, atropine, and acetylcholinesterase were determined in blood samples taken at intervals over a 6h period postinjection. After injection in anaesthetized pigs, both HI‐6 and atropine were absorbed rapidly and completely from the injection site. Therapeutic serum concentrations of HI‐6, arbitrarily taken as 4 μg mL−1, were reached within 1 min of intravenous and autoinjector administration, and within 5 min of intramuscular injection. The concentrations remained above this level for 3–4h. There were no significant changes in acetylcholinesterase activity, mean arterial blood pressure, or respiration frequency after injection of HI‐6 and atropine sulphate. The heart rates increased significantly after administration of the two drugs (cardioacceleration defined as ⩾ 5% increase in heart rate), regardless of the technique employed. Our results show that HI‐6 and atropine sulphate can be given intramuscularly by the new autoinjector with the same effectiveness and speed as when given intravenously. Irrespective of the injection technique, no overt signs of toxicity were observed at the drug con

ISSN:0142-2782    

DOI:10.1002/bdd.2510160804

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractWe investigated the biodistribution and antitumour activity of doxorubicin (ADM) encapsulated in liposomes (L‐ADM) after two administrations in tumour bearing mice. The effect of the first administration on phagocytic activity was also examined.The biodistribution of L‐ADM after the second dosing at an interval of 4d was remarkably different from that after the first. The concentration of ADM in plasma and tumour after the second injection was higher, but that in the liver was lower than after the first administration. This decrease in distribution to the liver is thought to have contributed to the difference in the biodistribution characteristics of L‐ADM. With regard to antitumour effect, the activity was similar between L‐ADM and a solution of ADM (F‐ADM).To investigate the effect of the first administration of L‐ADM on biodistribution, systemic phagocytic activity was measured after the injection of F‐ADM, L‐ADM, or ‘empty’ liposomes not containing ADM. F‐ADM and L‐ADM (7.5 mg ADM/kg body weight) reduced phagocytic activity to approximately 50% and 30% of control, respectively. This finding suggests that entrapment of ADM in liposomes enhances both the distribution of the drug to the reticuloendothelial system (RES) and its suppressive effect on RES activity.These results indicate that the decrease in RES activity by L‐ADM must be considered in estimation of the pharmacokinetics, antitumour activity, and toxicity of L‐ADM in clinical use when given by repeat administration or used in combination w

ISSN:0142-2782    

DOI:10.1002/bdd.2510160805

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractPharmacokinetic studies with antipyrine were carried out on beagle dogs to determine the consequence of hepatectomy on hepatic drug metabolizing capacity, the rate of hepatic regeneration, and the possible beneficial effect of hepatocellular transplantation. The drug (250 mg) was administered by short IV infusion in three groups of dogs (first group, 65% hepatectomy; second group, 65% hepatectomy with hepatocyte transplantation; third group 80% hepatectomy). Pharmacokinetic parameters of antipyrine were evaluated before surgery and within 10 d after surgery. Blood samples were taken at frequent intervals after drug administration and antipyrine was assayed in plasma by a specific HPLC method with UV detection. Before surgery, the mean elimination half‐life was about 1.1 h and total clearance averaged 6 L h−1. In dogs with 65% hepatectomy, no statistical differences in pharmacokinetic parameters of antipyrine appeared before or after surgery. When 65% hepatectomy was associated with hepatocyte transplantation, a significant increase in elimination half‐life and a significant decrease in total clearance were observed. The same statistical differences in the pharmacokinetic parameters were observed in the group with 80% hepatectomy. Transplantation of isolated hepatocytes into the spleen did not correct hepatocellular insufficiency. In this study, numerous laboratory tests were performed. A significant correlation was found between serum albumin, cholesterol, factor V, ALAT, total bilirubin, and ratio of aminoacids and the pharmacokinetic parameters of antip

ISSN:0142-2782    

DOI:10.1002/bdd.2510160806

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe plasma pharmacokinetics, and the urinary excretion, of terbinafine and its five main metabolites have been investigated after a single oral dose administration of 125 mg to 16 healthy subjects.In plasma, the highest concentrations are observed for the two carboxybutyl metabolites, with a predominance for the carboxybutylterbinafine. For this metabolite, as compared to terbinafine, theCmaxand AUC are 2.4 and 13 times higher respectively. The demethylterbinafine presents a plasma profile close to that of terbinafine. The two hydroxy metabolites are only found as glucuronide and are of minor importance. The apparent terminal half‐lives of terbinafine, demethylterbinafine, and the two carboxy metabolites appear to be similar (∼ 25h). As compared to the plasma concentration of total radioactivity observed after a single oral administration of the same dose of14C‐terbinafine, the parent drug and these five metabolites, account for more than 80% of the total radioactivity in plasma over the 0–48 h interval following administration.In urine, the major metabolite is demethylcarboxybutylterbinafine, which amounted to about 10% of the administered dose. Terbinafine and demethylterbinafine are only excreted as trace amounts in urine. Carboxybutylterbinafine and the two hydroxy metabolites are excreted in the range of 0.5–2% either as glucuronides or free. Urinary excretion over the 0–48h interval of terbinafine and of the five metabolites amounted to about 14% of the administered dose. This is far below the level of total radioactivity measured in urine over the same interval (∼ 57%), after administration of14C‐terbinafine. This shows in contrast to plasma, that numerous other metabolites are p

ISSN:0142-2782    

DOI:10.1002/bdd.2510160807

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractFor the purpose of selecting an animal model for the study of the aging effect on the pharmacokinetics of nalbuphine, the pharmacokinetic properties in young and in aged rabbits were reported. Thirty‐one healthy New Zealand white rabbits ranging in ages (mean) from three months to 43 months (six three months old, group I; nine eight months old, group II; nine 18 months old, group III; and seven 43 months old, group IV) were included in the study. After intravenous bolus injection of nalbuphine (10 mg kg−1) to each rabbit, plasma samples were collected and analysed for nalbuphine by a high‐performance liquid chromatography method. The plasma concentration—time data regarding nalbuphine were successfully fitted to a linear two‐compartment open model. The elimination half‐life of nalbuphine in rabbits increased significantly with age. Consequently, clearance decreased significantly with age. The parameter AUC0‐∞, which is derived from dose/clearance, increased significantly with age. The effect of aging on the pharmacokinetics of nalbuphine in rabbits is quite similar to that in humans. From the present study, it is concluded that rabbits may be suitable for the study of aging effects on the pharmacokinetic

ISSN:0142-2782    

DOI:10.1002/bdd.2510160808

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe protein binding of sotalol (STL) enantiomers was evaluated using an ultrafiltration technique with serum from young (32±2 years,n=5) and elderly (73±6 years,n=5) male and female humans, and young (8 weeks,n=4) and elderly (60 weeks,n=3) male Sprague—Dawley rats. Serum samples were collected and immediately frozen at −20°C. Within 1 week, the serum samples were thawed at room temperature, and adjusted to pH 7.4 using 0.05Mphosphate buffer, pH 5.0. Aliquots were spiked with 250 ng mL−1and 500 ng mL−1of each STL enantiomer, placed in ultrafiltration sets (Microsep, 30K molecular weight cut‐off), capped, equilibrated to 37°C, and centrifuged at 1850g for 1.5h at 37°C. Aliquots of ultrafiltrate and unspun serum were analysed for STL enantiomer concentration using a stereospecific HPLC assay. In all groups, bound fraction was less than 7% for both STL enantiomers. There were no significant differences in bound fraction between groups, or between enantiomers. Adsorption of STL enantiomers to the ultrafiltration device and membrane, evaporative loss of serum samples during centrifugation, and protein concentration in each ultrafiltrate sample were all negligible. It is concluded that the binding of STL in human and rat serum at therapeutic concentrations and physiological temperature and pH is negligible and non

ISSN:0142-2782    

DOI:10.1002/bdd.2510160809

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160810

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160811

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY