摘要:

AbstractRegional pharmacokinetics is the study of drug concentrations in specific regions of the body due to drug uptake and elution. Mathematical methods of interpreting regional pharmacokinetic data can vary greatly in their complexity depending on their intended use (i.e. to describe or predict), but must reinforce rather than replace experimental pharmacokinetics. ‘Black box’ analysis provides and empirical method for the study of complex pharmacokinetic systems using either statistical moment or linear systems analysis. However, these methods are only applicable to linear and time‐invariant systems, and ignore the large body of information concerning the physiological and physicochemical basis of regional pharmacokinetics. Clearance concepts are suitable for describing linear drug uptake processes, but mass balance principles have wider applications in describing the rate and extent of both drug uptake and elution. Compartmental models of a region can vary from single compartment descriptions based on the concept of venous equilibrium to complex multi‐compartmental models of the intra‐vascular, interstitial, and intracellular spaces, in which drug transport between compartments is a function of drug binding and ionization. Ultimately, as more regional pharmacokinetic information is obtained, more complex three dimensional models may be necessary such as those used to describe the uptake of oxygen from ca

ISSN:0142-2782    

DOI:10.1002/bdd.2510120102

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY

摘要:

AbstractThe effect of short term (7 days) and long term (28 days) pretreatment with the imidazole H2‐receptor antagonist, cimetidine (CMT), on the pharmacokinetics of 5‐fluorouracil (5‐FUra) has been studied in the rat and cynomolgus monkey. Short‐term pretreatment of rats with CMT significantly increasedt1/2,zby 29 per cent and AUC by 40 per cent: total body clearance was decreased by 30 per cent. Long‐term pretreatment exaggerated these effects. By contrast, short‐ and long‐term pretreatment with the furan H2‐receptor antagonist, ranitidine, caused no significant effect on 5‐FUra kinetics. In the monkey, 7 days pretreatment with CMT increasedt1/2,zby 32 per cent leaving other 5‐FUra kinetic parameters unchanged; 28 days pretreatment increased botht1/2,zby 41 per cent and AUC by 100 per cent with a decrease in total body clearance of 5‐FUra of 48 per cent. CMT, but not RNT, inhibited cytosolic dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5‐FUra catabolism. It is proposed that the observed effects of CMT on 5‐FUra kinetics are the result of inhibition of DPD. This interaction has the potential for increasing systemic drug toxicity and it is therefore advisable that where H2‐receptor blockade is administered concurrently with 5‐FUra that a non‐imidazole based H2‐receptor antagonist such as

ISSN:0142-2782    

DOI:10.1002/bdd.2510120103

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY

摘要:

AbstractA high‐performance liquid chromatographic method was developed to determine stobadin pharmacokinetics in dog and man. The relative bioavailability of stobadin dipalmitate compared with dihydrochloride was 46·4 per cent in dog. In man peak serum concentrations ranged from 12 to 289ng ml−1after a single oral dose of stobadin dipalmitate (0·79 to 2·5mg

ISSN:0142-2782    

DOI:10.1002/bdd.2510120104

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY

摘要:

AbstractA capillary gas chromatographic method with nitrogen specific detection is presented for measuring pseudoephedrine and its major metabolite norpseudoephedrine in urine after derivatization with trifluoroacetic anhydride. After the oral intake of 49·2 mg pseudoephedrine (ACTIFED®) the active substance is nearly quantitatively excreted in urine over a 48 hr period. From 1 to 7 per cent is metabolized to norpseudoephedrine. The intake of acetazolamide results in a suppression of the pseudoephedrine concentration for at least 12h. The diuretic effect after the intake of 1·51 mineral water could be compared with the effect obtained with 1 mg bumetanide and results in a decrease in pseudoephedrine concentration by a factor 4 for several hou

ISSN:0142-2782    

DOI:10.1002/bdd.2510120105

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY

摘要:

AbstractThe absorption characteristics of etretinate were examined in the Sprague‐Dawley rat with the use of thein situintestinal lumen perfusion model. Intestinal segments of 15–50cm were cannulated and perfused with etretinate solutions of 178–1405 μgml−1in a single‐pass manner at flow rates of 0·15–0·96 ml min−1. The intestinal effluent was collected and analyzed by HPLC for etretinate, as was blood that was drawn from the jugular vein. Despite its lipophilic nature, etretinate does not appear to be well absorbed from the rat intestine; the maximum fraction disappearing from the intestinal lumen was approximately 0·35. The absorption of etretinate appeared to be controlled by the aqueous diffusion layer. There was no evidence that the uptake of etretinate by the gastrointestinal membrane involved an active

ISSN:0142-2782    

DOI:10.1002/bdd.2510120106

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY

摘要:

AbstractThe present investigation was undertaken to examine the brain uptake kinetics of the central nervous system (CNS) stimulant pentylenetetrazol (PTZ) during postnatal development. This study represents part of an ongoing effort to develop an appropriate seizure model for investigations of anticonvulsant action in the developing rat. The systemic pharmacokinetics of PTZ were examined in male and female adult animals following both intravenous (IV) and subcutaneous (SC) injection. PTZ administered SC was absorbed rapidly and was completely bioavailable in both genders. No statistically significant gender‐dependent differences in the disposition of PTZ were identified. To examine the CNS uptake kinetics of PTZ, animals of four different age groups (5, 10, 20, and 60 days postnatal) received timed SC infusions of PTZ. Significant age‐related differences in the rate of uptake of PTZ into the CNS were observed. These differences paralleled the previously reported age‐dependent changes in the dose of PTZ required to elicit seizure activity. The results of this investigation indicate that the apparent age‐related change in sensitivity to the convulsant effects of PTZ is due in part to age‐dependent uptake of the convulsant into bra

ISSN:0142-2782    

DOI:10.1002/bdd.2510120107

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY

摘要:

AbstractEquations for the mean number of cycles through the peripheral system (R) and the mean transit time through the central compartment (MTTc) are derived for intravenous drugs with linear distribution and linear or nonlinear central elimination. ThisRis a function of distribution clearance (CLD), dose, and area under the plasma concentration–time curve (AUC). TheMTTcis a function of the central volume of distribution, CLD, dose, and AUC. The application of the proposed calculations ofRandMTTcwas illustrated by computer simulation

ISSN:0142-2782    

DOI:10.1002/bdd.2510120108

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY

摘要:

AbstractThis double‐blind randomized, crossover study was undertaken to determine the pharmacokinetic properties of nifedipine retard and atenolol when given separately, as a free or a fixed combination, compared with placebo in 15 healthy male volunteers. There was no difference between the three atenolol formulations in time to maximum blood concentration or elimination half‐life. The fixed combination showed significant differences in both maximum observed blood concentrations (+16 per cent) and total area under the curve (+16 per cent) compared to atenolol alone. Urinary recovery of unchanged drug from the fixed combination was also slightly increased but the difference was not statistically significant. Furthermore, statistical evaluation of the plasma pharmacokinetics of nifedipine retard and urinary recovery of nifedipine metabolite showed that all three formulations were indistinguishable. Thus, it is concluded that the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and that the bioavailability of both drugs in the fixed combination is equivalent to that of the single entit

ISSN:0142-2782    

DOI:10.1002/bdd.2510120109

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510120101

出版商:John Wiley&Sons, Ltd.    

年代:1991

数据来源: WILEY