摘要:

AbstractD, L‐3‐hydroxy‐3‐ethyl‐3‐phenylpropanamide (HEPP) is a synthetic drug with anticovulsant effects in a variety of seizure models. HEPP pharmacokinetics was studied after single 50 mg kg−1intravenous (IV), intraperitoneal (IP), and oral (PO) administration in male albino Wistar rats. The plasma concentration against time curves showed a biphasic decay pattern with a similar distribution phase and the same terminal rate constant (β = 0.22 h−1) by all three routes. The apparent volume of distribution at steady state (VSS= 0.80 L kg−1) indicates that HEPP is extensively distributed in extracellular tissues. This finding agrees very well with its low binding to plasma protein (mean bound fraction = 19.3 ± 1.1%). The systemic clearance (Cl) was very low (3.30mL min−1kg−1). The bioavailability after IP and PO administration was 0.80 and 0.60 respectively. In the pharmacokinetic‐pharmacodynamic studies a direct relationship was found between the protective effect of HEPP against pentylenetetrazole (PTZ) induced seizures and its concentration in plasma and/or brain. The concentrations at half‐maximal effect (EC50) with 95% confidence interval (Cl) were 70.6 (66–75.5) μg mL−1in serum and 60.1 (55.4–65.1) μg g−1in brain. There was a rapid uptake of HEPP into the brain, and after the distributive phase, the disappearances in plasma and brain were almost parallel [Cserum= 109 e−0.25t,r2= 0.95;Cbrain= 38 e2.53t+ 91 e−0.21t,r2

ISSN:0142-2782    

DOI:10.1002/bdd.2510160203

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractWe synthesized14C‐warfarin hexadecyl ether (14C‐WHE) by addition of a palmityl moiety to the hydroxyl group at the 4‐position of14C‐warfarin, a compound known to bind to serum albumin.14C‐WHE preferentially bound to the lipoproteins, low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL), in mouse plasma bothin vitroandin vivo.14C‐Warfarin mainly concentrated in the liver immediately after intravenous administration to mice bearing M5076 sarcoma, and was found at only low concentrations in other tissues including the tumour.14C‐WHE highly distributed to the tumour, in other tissues including the tumour.14C‐WHE highly distributed to the tumour, adrenal, and spleen, as well as the liver. These tissues coincided with those in which human125I‐LDL was vigorously incorporated. The results indicate that chemical modification of an agent, giving it high lipophilicity, will enable it to bind to lipoproteins after intravenous administration. These modifications raise the possibility of lipoproteins as endogenous targeting carriers into tumour cells, which have high

ISSN:0142-2782    

DOI:10.1002/bdd.2510160204

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractHEPP (D, L‐3‐hydroxy‐3‐ethyl‐3‐phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low toxicity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg−1. A biphasic disappearance pattern with a rapid distribution phase was observed in the plasma concentration versus time curve. The mean terminal half‐life (t1/2β) was the same after the three doses (3.4±0.15h) and the mean half‐lives of the distribution phase (t1/2α) were not significantly different after the three doses (0.09±0.02, 0.08±0.07, and 0.11±0.03 h for 8, 15, and 30 mg kg−1respectively). The mean AUC0‐∞values were 44.1±10.8, 72.1±8.8, and 127.4±23.2 μg h mL−1, respectively, showing a linear increase. The individual values of AUC0‐∞corrected for the administered dose (AUC0‐∞/D) were 0.29±0.04, 0.23±0.05, and 0.22±0.06 h mL−1. These values were not statistically different. Neither the mean residence time (MRT=4.55±1.50, 4.90±1.32, and 5.07±1.95 h), the steady state volume of distribution (Vss=0.86±0.11, 1.01±0.17, and 1.20±0.40 L kg−1) nor the systemic clearance (Cl=3.36±0.82, 3.53±0.44, and 4.02±0.68 mL min−1kg−1) showed significant differences between doses. The values ofVsssuggest that HEPP is distributed in the whole body fluid. The invariant pharmacokinetic parameters and the direct correlation between AUC0‐∞and the dose suggest that the

ISSN:0142-2782    

DOI:10.1002/bdd.2510160205

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe objective of this study was to quantify and model the degradation process of liposomes in peritoneal macrophages (PMs). Iodinated albumin (125I‐alb) was chosen to be the marker of liposome degradation. The time course of the degradation of free125I‐alb after pinocytosis by PMs followed first‐order kinetics with a half‐life of 23 min. The degradation of liposomally encapsulated125I‐alb was also quantified. Kinetic modelling of liposome degradation indicated the existence of two kinetically different processes, one with a half‐life of 13 min and the other with a half‐life of 7.5 h. Comparing the degradation of liposomal and free125I‐alb suggested that125I‐alb was delivered to lysosomes much faster through phagocytosis than pinocytosis. These results indicate that the intracellular degradation kinetics of pinosomes and phagosomes is different. This method can quantify the rate and extent of liposomal degradation in macrophages and provide kinetic information on the intracellular destiny of liposomally encap

ISSN:0142-2782    

DOI:10.1002/bdd.2510160206

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe dose proportionality and bioequivalence of the capsule formulations used in clinical trials and the proposed commercial formulations of stavudine were assessed in an openlabel, single‐dose, randomized four‐way crossover study in 16 asymptomatic HIV‐infected males. One capsule of stavudine (5, 10, 20, or 40 mg) was administered orally to each subject in each of the four treatment periods. Serial blood samples were collected for 10 h after each dose and the plasma was assayed for intact stavudine by a validated radioimmunoassay method. The plasma concentration‐time data were subjected to noncompartmental pharmacokinetic analysis. For doses ranging from 5 to 40 mg, meanCmaxand AUC0‐∞values were in the range of 110.36–889.34 ng mL−1and 246.46–1945.97 h ng mL−1respectively. The meanCmaxand AUC0‐∞of stavudine increased in a dose‐proportional manner. Irrespective of the dose, meanCmaxvalues were observed at a mediantmaxof 0.75 h or less. Meant1/2values were 1.97, 1.77, 1.67 and 1.66 h for the 5, 10, 20, and 40 mg capsules, respectively. For bioequivalence assessment,Cmaxand AUC0‐∞values were normalized to the 10 mg dose since these parameters were dose proportional. The 10 mg capsule formulation used in phase‐3 clinical trials was chosen as the reference. The relative bioavailability estimates and 90% confidence limits for the dose‐normalizedCmaxvalues with the 10 mg capsule as the reference were 86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20, and 40 mg capsules, respectively. The differences in the point estimates of the dose‐normalized AUC0‐∞values for the 5, 20, and 40 mg capsules relative to the 10 mg phase‐3 capsule were 1% or less, and the 90% confidence limits were all within 95–106%. These results indicate that stavudine exhibits linear pharmacokinetics and that the 5, 10, 20, and 40

ISSN:0142-2782    

DOI:10.1002/bdd.2510160207

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractSDZ FOX 988 (FOX 988) is being developed for the treatment of type II diabetes. The objective of this study was to examine the effect of the fat content of food on the pharmacokinetics and pharmacodynamics of FOX 988 following oral administration in the dog. In a randomized, cross‐over design, four dogs received a single 10 mg kg−1dose of14C‐FOX 988 suspension concomitantly with food containing 10% fat or 40% fat, or with the 10% fat food at 4 h post‐dose. Serial blood, urine, and fecal samples were collected for 96 h and analyzed for total radioactivity. Blod concentrations of 53–450, the active metabolite of FOX 988, were also determined. Serum concentrations of β‐hydroxybutyrate and glucose, pharmacological markers for the antidiabetic effects, were measured serially for 24 h after dosing. The animals receiving the low‐fat meal at dosing and at 4 h post‐dose exhibited similar extents of absorption, as shown by similar AUC values and urianry radioactivity recovery. Administration of the high‐fat meal at dosing significantly enhanced the absorption of FOX 988 and resulted in high blood concentrations of 53–450. However, no significant differences in the pharmacological activity of the drug were observed among

ISSN:0142-2782    

DOI:10.1002/bdd.2510160208

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractIn man,14C‐2‐ylcyanamide‐134‐thiadiazole (LY217896) accumulates into red blood cells (RBCs) where it is rapidly metabolized. Both in man andex vivo, within a few hours of administration of14C‐LY217896 at least two intracellular metabolites were detected within the RBCs using HPLC. These metabolites were never detected extracellularly. After 24 h no detectable radioactivity was found in the plasma and all the radioactivity was detected within the cellular fraction. All radioactivity was identified as a single peak within the RBCs, indicating the metabolite(s) to be highly polar compared to LY217896. Parent LY217896 was never detected within the RBCs at any time point, suggesting transport, either by diffusion or a carrier mediated mechanism, was the rate limiting step. Due to the nature of the preparation it was impossible to separately characterize uptake and biotransformation. Nevertheless, uptake/biotransformation was found to be temperature sensitive, sodium independent, and energy dependent. Both niacin and vitamin B6, but not nicotinamide, competitively blocked the uptake and subsequent intracellular metabolism of

ISSN:0142-2782    

DOI:10.1002/bdd.2510160209

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160210

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY