摘要:

AbstractSelegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. A sensitive fluorimetric assay based on ibhibition of rat brain monoamine oxidase‐B (MAO‐B)in vitrohas been developed to study the pharmacokinetics of selegiline. This method quantitates selegiline as low as 0.25 ng ml−1. The pharmacokinetics and relative bioavailability of selegiline were investigated in healthy volunteers following oral administration of 10 mg tablet or solution. A half‐life of approximately 70 min was observed following the administration of either dosage form. Although the two dosage forms exhibited a lag time, the absorption was rapid and peak plasma concentrations were observed between 30 and 45 min for the solution and 30 and 90 min for the tablets. Statistically no significant difference was found betweenCmax,Tmax, AUC0‐∞and MRT between the two dosage forms. Negligible renal clearance was found in both groups, but aparent oral plasma clearance was comparatively high and indicates rapid elimination of selegiline fr

ISSN:0142-2782    

DOI:10.1002/bdd.2510160703

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractStability of azosemide after incubation in various pH solutions, human plasma, human gastric juice, and rat liver homogenates, metabolism of azosemide after incubation in 9000g supernatant fraction of various rat tissue homogenates in the presence of NADPH, tissue distribution of azosemide and M1 after intravenous (IV) administration of azosemide, 20 mg kg−1, to rats, and blood partition of azosemide between plasma and blood cells from rabbit blood were studied. Azosemide seemed to be stable for up to 48 h incubation in various pH solutions ranging from two to 13 at an azosemide concentration of 10 μg mL−1; more than 93.4% of azosemide was recovered and a metabolite of azosemide, M1, was not detected. However, the drug was unstable in pH 1 solution: 75.8% of azosemide was recovered and 2.16 μg mL−1of M1 (expressed in terms of azosemide) was formed after 48 h incubation in pH 1 solution at an azosemide concentration of 10 μg mL−1. Azosemide was stable in both human plasma and rat liver homogenates for up to 24 h incubation at an azosemide concentration of 1 μg mL−1, and in human gastric juice for up to 4 h incubation at an azosemide concentration of 10 μg mL−1. However,‐all rat tissues stdied had metabolic activity for azosemide in the presence of NADPH, with heart having a considerable metabolic acitivity: approximately 22% of azosemide disappeared and 9.32 μg of M1 was formed per gram of heart (expressed in terms of azosemide) after 30 min incubation of 50 μg of azosemide in 9000g supernatant fraction of heart homogenates. The tissue to plasma ratios of azosemide (T/P) were greater than unity only in the liver (1.26) and kidney (1.74); however, M1 showed high affinity for all tissues studied except the brain and spleen when each tissue was collected at 30 min after IV administration of azosemide to rats. The equilibrium plasma to blood cell concentration ratios of azosemide were independent of azosemide blood concentrations: the values were 2.78–4.25 at azosemide blood concentrations of 1, 10, and 20 μg mL−1three rabbits. There was negligible ‘blood storage effect’ of azosemide, especially at low blood concentrations of azosem

ISSN:0142-2782    

DOI:10.1002/bdd.2510160704

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe inhibitory effect of the essential α‐aminoacid L‐leucine on the intestinal absorption of the antispastic drug baclofen was examined by means of anin siturat gut perfusion technique. When 0.5 mM baclofen solutions were perfused in the presence of increasing concentrations of the aminoacid (5–100 mM), the apparent absorption rate constant of the drug decreased as the initial leucine concentration increased. Higher leucine concentrations, however, did not completely abolish the absorption of the drug (at 100 mM of leucine, only 76% inhibition was observed). The interaction can be mathematically described as a complete competitive inhibition with a second component,K= 0.35 (±0.08)h−1,Ki= 0.25 (±0.09)mM, AIC= −97.02. In the light of some of the absorption features of the drug, however, the residual absorption of baclofen in the presence of high leucine concentrations should be attributed to another transport system not used by leucine.Apparent parameters characterizing absorption of leucine in the presence of baclofen (0.5mM) wereVm=61.02 (±5.46)mM h−1;Km=8.04 (±0.89)mM, and AIC=62.25. The results indicate that baclofen and leucine share some carriers in the intestinal absorption processes. Since leucine is an essential dietary aminoacid, and therefore a normal food component, this finding could be relevant in preventing interactions that would lead to a reduced oral bioavailability during

ISSN:0142-2782    

DOI:10.1002/bdd.2510160705

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractIn order to further examine the mechanism of the increase in the plasma propranolol concentration versus time curve (AUC) caused by ingestion of propranolol with food, we administered R, S‐propranolol tablets (0.5mg kg−1) orally to healthy human volunteers and dogs in the presence and absence of sensory exposure to food without ingestion (teasing). Six healthy human volunteers were fasted on one occasion and on the other they were presented with an appetising meal, without eating it (teasing protocol). There was a strong trend to a greater propranolol AUC in the teasing protocol (139.54 mg mL−1h−1fasting, 178.105 mg mL−1h−1teasing;p=0.1), and time of peak concentration (tmax) was significantly prolonged (80.22min and 120.32 min, respectively;p<0.03). Further studies were carried out in dogs who received R‐propranolol (2 mg kg−1) as an oral solution by gavage tube on four different occasions: fasting, following intragastric administration of a high‐value liquid meal, following teasing with food in the animal house at normal feeding time (high‐intensity teasing), and following teasing with food at a time and place not associated with feeding (low‐intensity teasing). There were no significant differences in pharmacokinetic parameters between the fasting and intragastric food protocols. Low‐intensity teasing resulted in significantly lower AUC and peak concentration (Cmax) compared with fasting (p<0.05), confirming food effect patterns known to occur in dogs. High‐intensity teasing resulted in significantly greater AUC andCmaxcompared with fasting (p<0.05), reproducing in dogs the increase in propranolol AUC known to occur with food ingestion in humans. These findings suggest that the mechanism of the ‘food effect’ may involve physiological responses to the sight and smell of food additional to mech

ISSN:0142-2782    

DOI:10.1002/bdd.2510160706

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractMycophenolate mofetil (MPM), a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA). The enzymatic and non‐enzymatic hydrolysis was studied in an artifical digestive fluid, rat plasma, and tissue homogenates. MPM was chemically stable in the artificial digestive fluid. In rat tissue homogenates and plasma, MPM was rapidly hydrolysed to MPA. The conversion rate of MPM to MPA in various rat tissue homogenates was in the order of liver>kidney>plasma>small‐intestinal epithelial cells. After the intravenous injection of MPM at 16.7 mg kg−1, the terminal elimination half‐life,‐t1/2β, was 4.74 ± 0.33 (mean ± SD)h, and the area under the plasma concentration versus time curve, AUC, was 48.78 ± 6.01 μg h mL−1. After intraduodenal (ID) administration of MPM at 16.7 mg kg−1,t1/2βwas 3.92 ± 1.05 h, and the AUC was 38.08 ± 8.30 μg h mL−1. The systemic availability of MPA after ID MPM dosing was 1.52 times higher than that after ID administration of MPA. This result supports the usefulness of MPM as an oral produrg of MPA as a ne

ISSN:0142-2782    

DOI:10.1002/bdd.2510160707

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractA study was performed in ten patients, stabilized with oxcarbazepine monotherapy (450–750 mg bid) for two weeks minimum, to investigate the possibility of using saliva to monitor the oxcarbazepine therapy. Thirteen paired blood and saliva samples were taken over 24h. The saliva samples were obtained after stimulation.The analysis performed on the data suggests a dose dependence for the relationship between plasma and saliva concentrations of the main active metabolite, 10, 11‐dihydro‐10‐hydroxycarbamazepine (MHD), and the importance of the type of stimulation for the saliva's production. Therefore it would be preferable to use plasma concentrations to monitor oxcarbazepine therapy, if ne

ISSN:0142-2782    

DOI:10.1002/bdd.2510160708

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractVarious factors most likely to influence the plasma protein binding of azosemide to 4% human serum albumin (HSA) were evaluated using equilibrium dialysis at the initial azosemide concentration of 10 μg mL−1. It took approximately 8h of incubation to reach an equilibrium between 4% HSA and isotonic phosphate buffer of pH 7.4 containing 3% dextran (the ‘buffer’) using a Spectra/Por 2 membrane (molecular weight cut‐off 12000–14000) in a water bath shaker kept at 37°C and a rate of 50 oscillations min−1. Azosemide was fairly stable both in 4% HSA and in the ‘buffer’ for up to 24h. The binding of azosemide to 4% HSA was constant (95.5 ± 0.142%) at azosemide concentrations ranging from 5 to 100 μg mL−1. However, the extent of binding was dependent on HSA concentration: the values were 88.4, 91.0, 92.2, 94.2, 94.9, 94.9, and 94.9% at albumin concentrations of 0.5, 1, 2, 3, 4, 5, and 6% respectively. The binding was also dependent on incubation temperature; the binding values were 97.0, 94.9, and 94.9% when incubated at 6, 28, and 37°C, respectively. The binding of azosemide was also influenced by buffers containing various chloride ion concentrations and buffer pHs. The binding values were 95.3, 94.9, and 93.6% for the chloride ion concentrations of 0, 0.249, and 0.546%, respectively, and the unbound values were 6.8, 5.1, 3.8, 3.4, and 3.3% for buffer pHs of 5.8, 6.4, 7.0, 7.4, and 8.0, respectively. The binding of azosemide was independent of the quantity of heparin (up to 40 UmL−1), AAG (up to 0.16%), sodium azide (NaN3, up to 5%), its metabolite, Ml (up to 10 μg mL−1), and antico

ISSN:0142-2782    

DOI:10.1002/bdd.2510160709

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160710

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY