摘要:

AbstractThe transfer of valproic acid (VPA, 2‐propylpentanoic acid) and its unsaturated active metabolite (2‐en, 2‐propyl‐2‐pentenoic acid) from plasma to liver has been studied in the mouse between 2 min and 6 h following oral administration of 50 mg of the sodium salts per kg body weight. Transfer of both compounds was extremely rapid. Liver concentrations of VPA were higher than those in plasma, while liver concentrations of 2‐en were lower than those in plasma. The low hepatic levels of 2‐en may be explained by extensive plasma protein binding of this metabolite. The liver/plasma concentration ratios were concentration‐dependent, indicating the presence of active transport mechanisms and/or saturation of plasma protein binding. Our results indicate that 2‐en should be further studied in regard to its potential for the induction of liver toxicity. The desirable low level of 2‐en reached in the liver, seen together with previously observed favourable‐anticonvulsant profile and low teratogenicity, would indicate that this compound may be a valuable alternativ

ISSN:0142-2782    

DOI:10.1002/bdd.2510060102

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractFurosemide was given to rats as five different i.v. bolus doses (2.5–100mg kg−1), or as an i.v. infusion to a steady‐state concentration in plasma of 14μg ml−1. The urinary furosemide excretion rate (ΔAe/Δt) and the diuretic effect (volume of urine) were measured. A parallel shift in the excretion—response curve was seen as a fivefold increase in (ΔAe/Δt)50((ΔAe/Δt) at half‐maximal effect) between the i.v. bolus doses from 2.5 to 40 mg kg−1. The slope factor did not change. During infusion, a decrease in efficiency to 20 per cent of the initial value was seen. These results are indicative of an acute tolerance development to the diuretic effect of furosemide. Some intrarenal feedback inhibition mechanism might be involved, as the extracellular fluid volume seems to be of great importance to the effect obtained. The resulting effect can be compared with the influence of a co

ISSN:0142-2782    

DOI:10.1002/bdd.2510060103

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractIt is shown that the intrinsic and steady‐state clearances and the values of Vm, and Km, of the Michaelis—Menten equation estimated via the sinusoidal perfusion model are different from the corresponding values estimated via the venous equilibration model. The liver blood flow rates estimated by two theories (from plasma data) are identical. The comparison was made using the single dose oral and intravenous and steady‐state oral plasma concentration—time data for verapamil in six subjects previously pu

ISSN:0142-2782    

DOI:10.1002/bdd.2510060104

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of valproic acid (VPA) was investigated in six healthy volunteers. This was done by monitoring total and free (unbound) valproic acid levels in the serum, and the amount of one of its metabolites, VPA glucuronide, in the urine as a function of time, after a single dose administration of the parent drug. VPA half‐life calculated from the urine data of the metabolite was shorter than the half‐life calculated from the blood data. About 15 to 20 per cent of the administered oral dose of VPA was excreted in the urine as VPA glucuronide. The average free fraction of VPA obtained in this study, by using the EMIT technique, ranged from 1.5 to 11.5 per cent with a mean value of 4.9 per c

ISSN:0142-2782    

DOI:10.1002/bdd.2510060105

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractFendosal(200 mg) was given orally to each of two separate groups of twelve healthy male volunteers on separate occasions to assess the influence of food or antacid on the bioavailability of fendosal. Blood samples (20ml) were drawn during 12 hours postdosing and fendosal plasma concentrations were quantitated by a validated fluorescence technique. Food was shown to have no significant effect (p>0.05) on fendosal bioavailability. However, the bioavailability of fendosal in the presence of an antacid was reduced by 80 per cent.In vitrostudies suggested that a complexation between unionized fendosal and the metal ions contained in the antacid may be responsible for the decrease in the rate and extent of absorption observedin vivo.

ISSN:0142-2782    

DOI:10.1002/bdd.2510060106

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractThe total body clearance (CL), renal clearance (CLR), and nonrenal clearance (CLNR) of caffeine from plasma were determined following the intravenous administration of caffeine (4mgkg−1) to ten healthy men (aged 66–86 years) on three separate occasions. Positive correlations were observed between CL and urine flow rate (UFR), between CLRand UFR, and between CLNRand UFR (r= 0.8947,p= 0.0002;r= 0.8832,p= 0.0003; andr= 0.8920,p= 0.0002, respectively). Previous studies have established similar relationships between CLRand UFR for caffeine and its initial dimethylxanthine metabolites; theophylline, theobromine, and paraxanthine. A relationship between CL and UFR has not been reported previou

ISSN:0142-2782    

DOI:10.1002/bdd.2510060107

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractBased on a two‐compartment organ model the total exposure in a target tissue, the mean tissue residence time and the peak time of the tissue concentration are evaluated in terms of tissue to blood partition coefficient and permeability coefficient (membrane permeability) of the drug, as well as the organ volume and blood flow. The total exposure is dependent upon the partition coefficient whereas the mean residence time is also affected by the permeability coefficient of the target organ. The peak time of tissue concentration following bolus intravenous injection appears to be mainly determined by the mean organ transit time and the time course of blood concentration. A tissue specific therapeutic ratio is defined using the concept of total exposure and the advantages of a local route of drug administration are discussed in this respec

ISSN:0142-2782    

DOI:10.1002/bdd.2510060108

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractThree separate Latin square crossover studies were conducted in beagles to examine the effect of a meal on the bioavailability of a ciglitazone tablet, suspension, and solution. In these studies, drug was administered to fasted animals with either 50ml water or with 180g Purina Dog Chow and 20g butter. The data indicated that the meal significantly increased the AUC by about 40 per cent for both the tablet and the suspension but had no significant effect on the solution treatment. Comparisons across studies indicated low bioavailability in fasted animals from either the tablet or suspension relative to the solution. When drug was co‐administered with a meal, however, bioavailability appeared to be independent of dosage for

ISSN:0142-2782    

DOI:10.1002/bdd.2510060109

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractBioavailability studies in fasted dogs with ciglitazone (CGZ), an oral hypoglycemic agent, suggested that an absorption window could contribute to the poor oral availability of CGZ. If so, propantheline bromide (PPB) could increase the residence time of CGZ at absorption sites and increase its bioavailability. Using this rationale, a Latin square study was conducted with CGZ in fasted dogs (n= 10) using treatments of a single 125mg tablet with and without 1.2 mg kg−1i.m. PPB. PPB was given in a single dose 1 h prior to administration of CGZ. Plasma concentrations of CGZ were assayed by HPLC. PPB significantly increased the AUC of CGZ by a ratio of 1.2 : 1 (p<0.01). PPB also increased Tmaxfrom 2–8 h (p<0.001), and appeared to produce first order absorption of CGZ.In a separate CGZ study using fasted dogs (n= 10), a single 125mg tablet was administered with and without i.v. metoclopramide HCI (MCP). A 10mg dose of MCP was given 15 min prior to dosing with CGZ and repeated 1 h after dosing. MCP increases GI motility and was expected to decrease residence time of CGZ. MCP had no effect on Tmax, but significantly decreased AUC by 8 per cent (p= 0.05). MCP also reduced Cmaxby 16 per cent (p= 0.06). Taken as a whole, these data suggest that the effect of meals to increase bioavailability of CGZ could be mediated at least in part, through an increase in GI residence t

ISSN:0142-2782    

DOI:10.1002/bdd.2510060110

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY

摘要:

AbstractAdriamycin‐loaded bovine albumin microspheres have been prepared by a technique that allows preparation and administration to animals on the same day. Criteria adopted for injection were that microspheres should be stable and of a size such as to become trapped in capillary beds. These conditions were fulfilled by preparing microspheres using glutaraldehyde concentrations greater than 0.5 per cent and the appropriate combination of stirring speed and continuous phase viscosity. After systemic administration rats were sacrificed at intervals and major visceral organs examined for entrapped microspheres and serum for released drug. Microspheres sieved out in the first capillary bed encountered, the lung, then following biodegradation they disappeared at rate dependent on the amount of cross‐linking agent used in their preparation. In contrast to bolus injection, serum drug levels after microsphere administration indicated an initial rapid release followed by a more protracted phase lasting at least 24 h. This latter observation is consistent with drug release during biodegradation of carr

ISSN:0142-2782    

DOI:10.1002/bdd.2510060111

出版商:John Wiley&Sons, Ltd.    

年代:1985

数据来源: WILEY