摘要:

AbstractThe pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.), 1 mg/100 g body weight, and oral administration, 2 mg per 100g body weight, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate‐salt‐induced hypertensive rats (DOCA‐salt rats). After i.v. administration, the 8 h urinary excretion of furosemide/g kidney (397 versus 572 μg) was significantly lower and the non‐renal clearance (5.78 versus 3·94 ml min−1kg−1) was significantly faster in SHRs of 16 weeks of age than in age‐matched control Wistar rats. This suggested that the nonrenal metabolism of furosemide could be faster in SHRs of 16 weeks of age than in age‐matched control Wistar rats, and this could be supported by the significantly greater amount of 4‐chloro‐5‐sulphamoyl anthranilic acid, a metabolite of furosemide, excreted in 8 h urine as expressed in terms of furosemide (11·1 versus 4·79% of the i.v. dose) in SHRs. It could also be supported at least in part by a study of liver homogenate; the amount of furosemide remaining per gram of liver after 30 min incubation of 50μg of furosemide with the 9000g supernatant fraction of liver homogenate was significantly smaller (40·4 versus 43·7μg) in SHRs of 16 weeks of age than in age‐matched Wistar rats. The greater metabolic activity of furosemide in liver may also be supported by the result that the amount of hepatic cytochrome P‐450 (0·7013 versus 0·5186 nmol/mg protein) and the weights of liver (3·52 versus 2·93% of body weight) were significantly greater in SHRs of 16 weeks of age than in age‐matched Wistar rats. After i.v. administration of furosemide, the 8 h urine output (9·93 versus 16·5 ml) and 8 h urinary excretion of sodium (1·21 versus 2·05 mmol) and chloride (1·37 versus 2·17 mmol) per gram of kidney in SHRs of 16 weeks of age were lower than those in age‐matched Wistar rats, this could be due to the significantly smaller amount of furosemide excreted in 8 h urine per gram of kidney. After oral administration, the pharmacokinetics and pharmacodynamics of furosemide were not significantly different between SHRs and the control Wistar rats of 16 weeks of age. After i.v. and oral administration of furosemide, there were no significant differences in the pharmacokinetics and pharmacodynamics between DOCA‐salt rats and control SD rats of 16 weeks of age except for the significantly lower urinary excretion of potassium per gram of kidney in DOCA‐salt rats. On the other hand, the 8 h urinary excretion of furosemide and non‐renal clearance were not significantly different between SHRs of six weeks of age and age‐matched control Wistar rats after i.v. administration of furosemide. Since the non‐renal metabolism of furosemide was not faster in either DOCA‐salt rats of 16 weeks of age or SHRs of six weeks of age than that in the respective age‐matched control group, the faster non‐renal metabolism of furosemide in SHRs of 16 weeks of age could be due to the physiological factor from the chronic phase of hypertension in SHRs, and could not be due

ISSN:0142-2782    

DOI:10.1002/bdd.2510150302

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractIn order to determine the potential pharmacokinetic drug interaction between ranitidine and diltiazem (DTZ), each of ten male beagle dogs, age 2·7–4·0 years, weight 13–16 kg, received a single oral dose of sustained release DTZ with and without previous multiple oral doses of ranitidine (150 mgbidfor five doses). The dog was selected as the animal model because the pharmacokinetics and metabolism profiles of DTZ are similar to those in humans and because sustained release DTZ capsules can be administered with ease to this species. Following the oral dose of DTZ, blood samples (5 ml each) were obtained via a cephalic vein at 0 (just before dosing), 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 30, 36, and 48 h after the dose. Urine samples were collected for 48 h post dose. Plasma and urine concentrations of DTZ and its major metabolitesN‐monodesmethyl DTZ (MA), deacetyl DTZ (M1), and deacetylN‐monodesmethyl DTZ (M2) were determined by HPLC. Pharmacokinetic parameters were calculated by non‐linear curve fitting, and the effect of ranitidine was evaluated by two‐factor analysis of variance (ANOVA). Pre‐treatment of the animals did not significantly alter the disposition of DTZ (p>0·05). Similar to the results reported in clinical studies, there were large variations in the plasma and urine concentrations of DTZ and its major metabolites among the beagle dogs. The effect of ranitidine on the disposition of DTZ was

ISSN:0142-2782    

DOI:10.1002/bdd.2510150303

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe purpose of this study is to propose a new method for quantitative evaluation of liposome degradation in serum. The time course of liposome degradation in rat serum was monitored continuously, using 6(5)‐carboxyfluorescein as an aqueous phase marker. The degradation curves exhibited three characteristic phases: lag time, degradation, and plateau. This curve was described by a kinetic model with three parameters: lag time (τ), first‐order degradation rate constant (k), and maximum degradation (α). The rate and extent of the degradation of liposomes were evaluated separately in terms ofkand α, respectively. The effects of size and concentration of liposomes on their degradation kinetics were examined using this method. Bothkand α increased with increasing liposomal size. The increased affinity of larger liposomes for complement was suggested to increase bothkand α. On the other hand, α decreased with increasing liposomal concentration without alteringk. The decreased extent of degradation was considered to result from the depletion of complement components. There was no significant effect of size and concentration of liposomes on τ. Quantitative evaluation of the rate and extent of degradation of liposomes will provide deeper insights into the interaction between liposomes and serum components, and basic information on liposomes as potential dru

ISSN:0142-2782    

DOI:10.1002/bdd.2510150304

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

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),versus1626 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

ISSN:0142-2782    

DOI:10.1002/bdd.2510150305

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

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 increasedCmax(59%), an increasedt1/2(141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed fortmaxand 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 fun

ISSN:0142-2782    

DOI:10.1002/bdd.2510150306

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe oral bioavailability of aluminium was compared after administration of 1 g sucralphate as either a tablet or a suspension (1 g/5 ml) in a crossover study in 16 healthy volunteers. Aluminium levels were detectable in all subjects pre‐dose (21.4±8·8 μg 1−1before tablet; 21·4±7·4 μg 1−1before suspension) and there was a measurable increase in the plasma concentrations of aluminium in all subjects after administration of the suspension, and in 14 of the subjects after administration of the tablet formulation, withCmaxreached within the first 8 h in most subjects. Plasma levels were still elevated 72 h after dosing. The variability in plasma levels of aluminium was significantly higher after administration of the suspension (CV 39–53%) than after administration of the tablet (CV 29–44%), reflecting greater absorption of aluminium from the suspension formulation in three subjects. Similarly, the variance of theCmax, AUC(0–72 h), and AUC(0–∞)(for both the raw data and the baseline adjusted data) were all higher for the suspension than for the tablet. A point estimate of the difference of the pharmacokinetic parameters (determined from the median of the arithmetic Walsh averages) indicated little or no difference inCmax,Tmax, or AUC(0–∞)in the two formulations. In summary, the performance of the suspension formulation of sucralphate is more variable than the tablet formulationin vivoand some patients may therefore have higher circulating levels of aluminium on therapy with

ISSN:0142-2782    

DOI:10.1002/bdd.2510150307

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510150301

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY