摘要:

AbstractThein situ, perfused rat liver model was used to investigate the effect of three H2receptor antagonists on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H2‐receptor antagonist‐treated groups) of male Sprague‐Dawley rats (300–350 g). All animals received CyA, 2.5 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg), or famotidine (0.4 mg). Perfusated and bile samples were collected and assayed for CyA, AM1, and the H2receptor antagonists by HPLC. Results indicated that CyA perfusate concentrations in the controls and cimetidine and ranitidine‐treated groups were not significantly different, although levels in the famotidine group were significantly higher at all times (p<0.05), except 30 min, compared to the controls. However, examination of the AM1 perfusate and bile data and the apparent metabolic clearance data indicated that CyA metabolism was still occurring, despite the presence of the H2receptor antagonist. It is suggested that the absence of a interaction may be attributed to a lack of specificity of the H2receptor antagonists for CYP3A, the isoenzyme responsible for CyA m

ISSN:0142-2782    

DOI:10.1002/bdd.2510160903

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractSodium mercaptoundecahydrododecaborate or BSH is an important compound for boron neutron capture therapy (BNCT). The total clearance and steady state volume of distribution of BSH in humans and in laboratory animals were analyzed as a function of species body weight using the allometric equation for interspecies scaling. Significant linear relationships were obtained between log CLt(L h−1) and logW(kg) (r=0.972;p=0.028) as well as logVSS(L) and logW(kg) (r=0.999;p=0.0005). The corresponding allometric equations were CLt=0.127W0.68andVSS=1.557W0.87, respectively. BSH clearance in various species was shown to be a constant fraction (0.26) of creatinine clearance, the relationship being independent of body weight. Thus BSH clearance in various species occurred at similar pace when measured by a physiological parameter (creatinine clearance) rather than chronological time. Interspecies scale‐up of plasma concentration—time data for the four species using a complex Dedrick plot resulted in similar profiles. Our results indicate that the BSH data obtained in laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical st

ISSN:0142-2782    

DOI:10.1002/bdd.2510160904

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe relationship between antibronchospasmic, tachycardiac, or hypokalaemic effects and plasma concentration of L‐isoproterenol (ISP) hydrochloride was investigated in guinea‐pigsin vivo. ISP was infused at the rate of 10, 30, 50, 100, and 300 ng kg−1min−1. The antibronchospasmic effect was expressed as the attenuation of methacholine‐induced bronchospasm. The EC50values of ISP for antibronchospasmic and tachycardiac effects were 5.12 nM and 3.95 nM, respectively. Although they were comparable to the values reportedin vitro(7.23–0.358 nM, 1.77 nM), the concentration response relationship of ISP for antibronchospasmic effect was quite steep with a slope factor of more than six. Moreover, a decrease in plasma potassium level was not clearly detected. The experimental procedure in our present study was useful for evaluating antibronchospasmic and tachycardiac effects of be

ISSN:0142-2782    

DOI:10.1002/bdd.2510160905

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe enantioselective pharmacokinetics of a new anxiolytic, pazinaclone (DN‐2327), and its active metabolite, M‐II, were studied in animals. In rats and dogs given racemic pazinaclone intravenously, the total clearance and volume of distribution of (S)‐pazinaclone were lower than those of (R)‐pazinaclone, whereas the opposite results were obtained in monkeys. The differences in disposition were consistent with enantioselective protein binding, where the unbound fraction was greater for (R)‐pazinaclone than that for the (S)‐enantiomer in rats and dogs; the reverse was noted in monkeys. Lower clearance and distribution for (S)‐pazinaclone in rats and dogs, and for the (R)‐enantiomer in monkeys, resulted in comparable plasma profiles for the pazinaclone enantiomers and thereby those of the corresponding enantiomers of M‐II. The unbound clearance (CLu) of (S)‐pazinaclone was, however, greater than that of the antipode in rats and dogs and the CLuof each enantiomer was similar in monkeys. Thus, enantioselectivity in the kinetics of (S)‐ and (R)‐pazinaclone appears to reside largely in plasma binding differences and is unrelated to variations in intrinsic clearance. The first‐pass metabolism of (S)‐ and (R)‐pazinaclone on oral administration of the racemate was enantioselective, with respective bioavailabilities of 1.7 and 0.8% in rats, 10.4 and 1.9% in dogs, and 0 and 11.4% in monkeys. Therefore, the enantioselectivity was more

ISSN:0142-2782    

DOI:10.1002/bdd.2510160906

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractVarious factors influencing the plasma protein binding of YH‐439 to 4% human serum albumin (HSA) were evaluated using the equilibrium dialysis method at the initial YH‐439 concentration of 2 μg mL−1. It took approximately 12 h of incubation to reach an equilibrium between 4% HSA and isotonic phosphate buffer of pH 7.4 containing 3% of dextran (‘the buffer’) using a Spectra/Por 2 membrane (molecular weight cut‐off, 12 000–14 000) in a water bath shaker kept at 37. C and at a rate of 50 oscillations min−1. YH‐439 was fairly stable both in 4% HSA and in the ‘buffer’ for up to 24 h incubation. The binding of YH‐439 to 4% HSA was constant (97.4 ± 0.55%) at YH‐439 concentrations ranging from 0.5 to 10 μg mL−1. However, the extent of binding was dependent on HSA concentrations: the values were 90.7, 94.7, 96.7, 97.0, 97.0, 97.1, and 97.5% at HSA concentrations of 0.5, 1, 2, 3, 4, 5, and 6%, respectively. The plasma protein binding decreased with increasing incubation temperature: the binding values were 98.2, 97.6, 97.2, and 96.8% when incubated at 10, 21, 26, and 37°C, respectively. The binding of YH‐439 was also influenced by the chloride concentration in the buffer: the binding values were 94.5, 97.0, and 96.8% for the chloride concentrations of 0, 0.249, and 0.546%, respectively. The binding of YH‐439 was also dependent on the buffer pH: the percentages of free fraction were 6.0, 4.1, 3.8, 2.8, 2.7 and 2.8% for the buffer pHs of 5.0, 6.0, 6.5, 7.0, 7.4, and 8.0, respectively. The free fraction of YH‐439 was slightly increased by the addition of heparin (up to 40 U mL−1), sodium azide (NaN3, up to 0.5%), and its metabolites. The protein binding of YH‐439 was influenced neither by AAG, acetylsalicylic acid, or sulphisoxazole, nor by the addition of citrate or EDTA. The free fractions of YH‐439 in rabbit (4.2%) and dog (4.7%) plasma seemed to be h

ISSN:0142-2782    

DOI:10.1002/bdd.2510160907

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractBased on the convolution integral, equations have been drived for the ratio of the first to the zeroth moments of the plasma concentration—time curve (AUMC/AUC) parameters for a drug (p) undergoing first‐pass and reversible metabolism and its reversible metabolite (m). According to these equations, the AUMC/AUC of a drug administered orally and of its reversible metabolite can be related to the mean absorption times, the ratios of the fraction of the dose entering the systemic circulation to the bioavailability, the first‐time fractional conversion of each compound, and the AUMC/AUC ratios after intravenous administration of each compound. The proposed approach allows a more generalized derivation method for AUMC/AUC of a drug administered orally and undergoing first‐pass and reversible metabolism. It is also applicable to any other extravascula

ISSN:0142-2782    

DOI:10.1002/bdd.2510160908

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160909

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY