摘要:

AbstractIn addition to metabolic differences, the anatomical, physiological, and biochemical differences in the gastrointestinal (G.I.) tract of the human and common laboratory animals can cause significant variation in drug absorption from the oral route. Among the physiological factors, pH, bile, pancreatic juice, and mucus and fluid volume and content can modify dissolution rates, solubility, transit times, and membrane transport of drug molecules. The microbial content of the G.I. tract can significantly affect the reductive metabolism and enterohepatic circulation of drugs and colonic delivery of formulations. The transit time of dosage forms can be significantly different between species due to different dimensions and propulsive activities of the G.I. tract. The lipid/protein composition of the enterocyte membrane along the G.I. tract can alter binding and passive, active, and carrier‐mediated transport of drugs. The location and number of Peyer's patches can also be important in the absorption of large molecules and particulate matter.While small animals, rats, mice, guinea pigs, and rabbits, are most suitable for determining the mechanism of drug absorption and bioavailability values from powder or solution formulations, larger animals, dogs, pigs, and monkeys, are used to assess absorption from formulations. The understanding of physiological, anatomical, and biochemical differences between the G.I. tracts of different animal species can lead to the selection of the correct animal model to mimic the bioavailability of compounds in the human.This article reviews the anatomical, physiological, and biochemical differences between the G.I. tracts of humans and commonly used laboratory animal

ISSN:0142-2782    

DOI:10.1002/bdd.2510160502

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractA multiple‐dose bioequivalence study with six healthy human volunteers was conducted. The bioavailability of an experimental controlled release tablet containg pseudoephedrine was compared with a marketed controlled release pseudoephedrine capsule in a three‐way crossover study. Plasma samples, collected serially after oral drug administrtion, were analyzed for pseudoephedrine content using a specific HPLC method with UV detection. The bioavailability parameters, area under the concentration‐time curve (AUC), maximum plasma concentratonCmax, and time to peak (Tmax) were obtained from the plasma concentraton—time data. Additionally, model independent pharmacokinetic parameters were estimated. Analysis of variance of the data revealed no statistically significant differences between the test and the reference formulation. The presence of guaifenesin in the sustained release tablet did not influence pseudoephedrine bioavailability. The relative bioavailability of the tablet dosage form with respect to the capsule was found to be 100.8%. Classical and Westlake 95% confidence limits as well as the two one‐sidedttest, proposed by Schuirmann, and the Anderson—Hauck power analysis supported the inference that the two formulations demonstrated comparable bioavailability, even in the presence of guaifenesin.Using a non‐linear regression program, it was found that the parmacokinetics of pseudoephedrine followed a simple one‐compartment disposition model with no lag time. Additionally, anin vitro—in vivocorrelation, based on the estimation of cumulative relative fraction absorbed, was developed between the absorption of pseudoephedrine in humans and thein vitr

ISSN:0142-2782    

DOI:10.1002/bdd.2510160503

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractInfectious excerbations of COPD are generally due toStreptococcus pneumoniae, Haemophilusspeicies, and other Gram‐negative bacteria. Ofloxacin has potent activity against Gram‐negative species but is less effective against Gram‐positive species includingStreptococcus pneumoniae. It has also been shown that the administration of ambroxol increases the concentration of some antibiotics in pulmonary tissues. The aim of the study was to determine whether ambroxol increases the bronchial tissue concentrations of ofloxacin to a level exceeding the MIC90of the bacterial species less susceptible to ofloxacin. 24 patients with COPD were randomized in two groups. Drug regimens of ofloxacin alone (200 mg twice daily) or ofloxacin (200 mg twice daily) + ambroxol (30 mg thrice daily) were administered over 10d. A fibroscopy was performed on day 10 with bronchial biopsies and broncho‐alveolar lavage. At steady state, concentrations of drug in plasma and bronchial samples were assayed by HPLC with fluorometric detection. There was no significant difference in the bronchial levels of ofloxacin between the two groups; however, in alveolar cells, ofloxacin concentration was three times higher in the group with ambroxol. Ambroxol does not increase ofloxacin concentrations in bronchial tissue because high concentrations are already present in t

ISSN:0142-2782    

DOI:10.1002/bdd.2510160504

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractIn an open randomized crossover study, the pharmacokinetics and bioavailability of the selective β1‐adrenoceptor antagonist talinolol (Cordanum®—Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC‐MS. At the end ofinfusiona peak serum concentration (Cmax) of 631 ± 95 ng mL−1(mean ± SD) was observed. The area under the serum concentration‐time curve from zero to infinity (AUC0‐∞) was 1433 ± 153 ng h mL−1. The following parameters were estimated: terminal elimination half life (t1/2), 10.6 ± 3.3 h; mean residence time, 11.6 ± 3.1 h; volume of distribution, 3.3 ± 0.5 L kg−1; and total body clearance, 4.9 ± 0.6 mL min−1kg−1. Within 36 h 52.8 ± 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 ± 0.18% as hydroxylated talinolol metabolites in urine. Afteroraladministration aCmaxof 168 ± 67 ng mL−1was reached after 3.2 ± 0.8h. The AUC0‐∞was 1321 ± 382 ng h mL−1. Thet1/2was 11.9 ± 2.4 h. 28.1 ± 6.8% of the dose or 55.0 ± 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 ± 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 ± 15% (95% confidence interval, 36–69%). Talinolol does not undergo a relevant first‐pass metabolism, and its reduced bioavailability results from incomplete absorption. Talinolol disposition is not found to

ISSN:0142-2782    

DOI:10.1002/bdd.2510160505

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractIn a double‐blind, placebo‐controlled, single‐dose ascending pharmacokinetics and tolerance study, we evaluated the bispyridinium oxime HI‐6 dichloride monohydrate (62.5, 125, 250, and 500 mg), administered intramuscularly with atropine sulphate, 2 mg, in 24 healthy male volunteers. The plasma HI‐6 peak concentration (Cmax) and area under the concentration—time curve (AUC) demonstrated linear pharmacokinetics with low intradose variability, suggestive of uniformity of effect among subjects. HI‐6 (500 mg) attained plasma drug concentrations that appeared adequate for practical use as an antidote. The mean ± SD time to maximum plasma HI‐6 concentration (tmax= 0.69 ± 0.21 h,n= 16), and absorption half‐life (t/2a= 0.17 ± 0.05 h) indicated rapid onset of effect. The volume of distribution (Vd= 0.25 ± 0.04 L kg−1TBW) approximated the extracellular fluid volume. A high total body clearance (CL = 252 ± 52 mL min−1) and short apparent elimination half‐life (t/2e= 1.15 ± 0.19 h) were expected for this polar quaternary ammonium drug. The renal clearance (CLr= 137 ± 33 mL min−1), which approximated the expected glomerular filtration rate, and 24 h urinary excretion of unchanged drug (55 ± 10%) indicated substantial non‐renal elimination. Blood pressure, heart rate, respiratory rate, electrocardiographic parameters, mental acuity, and vision were not altered. Adverse events and changes in serum, urine and semen laboratory tests were mild. The pharmacokinetics, safety, and apparent efficacy of HI‐6 suggest it may be a superior oxime a

ISSN:0142-2782    

DOI:10.1002/bdd.2510160506

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractSerum and urine kinetics of unchanged tiracizine (T), a new class I antiarrhythmic agent, and three metabolites (M1, 2, and 3) were assessed in eight healthy extensive metabolizers after a single oral administration of 50 mg tiracizine and during steady state (50 mg b.i.d.). Additionally, tiracizine‐induced ECG changes were measured. Considerable accumulation of M1 and M2 was observed during repeated dosing (M1,Cmax,ss= 391.8 ng mL−1againstCmax,sd= 132.8 ng mL−1; M2,Cmax,ss= 143.2 ng mL−1againstCmax,sd= 25.8 ng mL−1). However, significant increases of AUC (AUCτ = 261.9 ng h mL−1against AUC0–∞,sd= 182.9 ng h mL−1),Cmax(Cmax,ss= 75.9 ng mL−1againstCmax,sd= 56.9 ng mL−1) andt1/2β(t1/2β,ss= 4.0 h againstt1/2β,sd= 2.4 h) of the parent compound indicate non‐linear kinetics. The significant decrease in renal clearance of all four substances as well as the decrease of non‐renal tiracizine clearance with repeated dosing led to the assumption that non‐linearity is due to saturable renal excretion and a fall in intrinsic tiracizine clearance. PQ time was prolonged significantly during steady state and culminated at thetmaxof the parent compound, whereas there was no change in any ECG parameter after a single‐dose a

ISSN:0142-2782    

DOI:10.1002/bdd.2510160507

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160508

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY