摘要:

AbstractFive methods of absorption rate (Ka) estimation were compared using data from a previously reported bioavailability study: Wagner‐Nelson (WN), asymptotic WN (AWN), the Hendeles‐Weinberger modification of the WN (HW), nonlinear regression performed on plasma concentration vs time data with fixed elimination rates (NL), and nonlinear regression performed on the cumulative sum of AUCs obtained during WN analysis (AUCNL). The maximum plasma concentration (Cmax) and the time at whichCmaxoccurred (Tmax) were predicted with each method's respectiveKa's, and these were compared to observed values. The WN and HW were consistently biased in their predictions ofCmaxandTmax, providing slowerKa's than any of the other methods. AWN could only be used for the reference treatment. Both NL and AUCNL provided unbiased estimations, but AUCNL had a high level of imprecision. With this set of data, only NL was an acceptable method for accurately estimatin

ISSN:0142-2782    

DOI:10.1002/bdd.2510100203

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractPlasma kinetics and renal excretion of iodopyracet (3·0 g, adminstered i.v.) with and without concomitant administration of probenecid were studied in the beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid. A physiologically based kidney model is proposed comprising all the functional characteristics of the kidney that determine the excretion of iodopyracet, i.e. renal plasma flow, urine flow, protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. Renal clearance of iodopyracet is characterized by supply‐limited elimination at low plasma concentrations and capacity‐limited elimination at high plasma levels. The interactioin with probenecid could be adequately described with the model by competitive inhibition of the carrier‐mediated uptake of iodopyracet into the tubular cells. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of iodopyracet within the cells, which was clearly diminished in the presence of prob

ISSN:0142-2782    

DOI:10.1002/bdd.2510100204

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe disposition of primaquine (0·75 mg, 5 μCi) has been investigated in the isolated perfused rat liver (IPRL) preparation alone and concurrently with mefloquine. In both groups, primaquine concentrations declined exponentially. There were no significant differences between the respective groups in the half‐lives (2·5 ± 1·5, 2·2 ± 1·1 h), AUCs (0·43 ± 0·14, 0·372 ± 0·096 μg·h ml−1), clearances (19·0 ± 5·4, 21·1 ± 4·2 ml h−1), and apparent volume of distribution (78·9 ± 28·1, 76·2 ± 31·7 ml). In the presence of mefloquine, total bile production was significantly reduced (1244·5 ± 317·1 μl) compared with primaquine alone (1621·5 ± 174·2 μl). Hence, although significantly less radioactivity ([3H]) was eliminated in bile in the presence of mefloquine (30·0 ± 7·9 per cent versus 39·9 ± 3·6 per cent) there was no significant difference between the groups in [3H]/μl bile eliminated. Significantly more [3H] was recovered from the livers of the mefloquine/primaquine group. This was underlined by the significantly greater proportions of [3H] recovered from the 10000 g pellet, 10000 g supernatant and 105000 g supernatant in the presence of mefloquine compared with primaquine alone. Hence, it appears mefloquine had little or no direct action or primaquine metab

ISSN:0142-2782    

DOI:10.1002/bdd.2510100205

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractA crossover study in 18 subjects evaluated the plasma concentration–time profile of two different 20 mg sustained‐release (SR) methylphenidate (MPH) tablets administered before breakfast, compared to a 10 mg immediate‐release (IR) tablet administered before breakfast and again 5 h later, before lunch. Plasma MPH concentrations were determined using a sensitive and precise gas chromatography–mass spectrometry method, incorporating a deuterated internal standard. The mean peak MPH concentration was 6.4 ng ml−1for the IR product versus 4·6 ng ml−1and 4·8 ng ml−1for the two SR formulations. Peak concentrations occurred at 3·3 h after dosing with the SR products, compared to 1·5 h after the first dose of the IR product. The extent of absorption for the three products, as determined from areas under the plasma concentration‐time curves, were within 5 per cent of each other. There was no significant difference in rate or extent of absorption between the

ISSN:0142-2782    

DOI:10.1002/bdd.2510100206

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractHemofiltration is a relatively new technique for removing toxic substances from the body. Unlike hemodialysis or hemoperfusion, the driving force behind hemofiltration is ultrafiltration. There have been several studies examining the clearance of drugs by hemofiltration but to date no study has investigated in a systematic way the effects of protein binding, perfusate flow, transmembrane pressure, and the duration of treatment on drug clearance by hemofiltration. The influence of these factors on the hemofiltration clearance of three sulfonamides with differing degrees of protein binding was investigated. It was found that hemofiltration drug clearance decreased with the duration of hemofiltration and protein binding but increased with perfusate flow and transmembrane pressure.

ISSN:0142-2782    

DOI:10.1002/bdd.2510100207

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe distribution, metabolism, and pharmacokinetics of physostigmine (Phy) and the time course of butyrylcholinesterase (BuChE) in plasma and cholinesterase (ChE) activity in brain and muscle and their relationship to Phy concentration were described after oral administration of3H‐Phy (650 μg kg−1) to rats. Physostigmine concentration vs time data was analyzed by nonlinear computer fitting program using one‐compartment model. The absorption rate constant (ka) and elimination rate constant (ke) were found to be 0·1 ± 0·07 min−1and 0·036 ± 0·024 min−1, respectively.Cpmaxandtmaxwere 3·3 ng ml−1and 16 min. The clearance (Cl) was found to be 80·9 ml min−1kg−1. Half‐life of Phy in brain, muscle, and liver were 33·4min, 22·5, and 28 min, respectively. The bioavailability (F) was calculated to be 0·02 and the extraction ratio was found to be 0·98 indicating the ‘first pass’ effect. Butyrylcholinesterase activity in plasma was 76 per cent at 15 min and this activity did not change significantly up to 120 min. However, Phy concentration in plasma was very low; 2·89 ng ml−1at 15 min and declined to 0.71 ng ml−1at 90 min. Physostigmine concentration in brain peaked at 22 min to 2·85 ± 1·09 ng g−1and declined to 0·33 ± 0·11 ng g−1at 60 min. Cholinesterase activity in brain was 96 per cent, 82 per cent and 89 per cent at 10, 45, and 120 min, respectively. Physostigmine concentration in muscle was very low and the ChE activity in the muscle was 66·4 per cent of control at 45 min. The time course of Phy metabolism indicated that at 5 min most of the RA in the tissues was due to metabolites accounting for 94·6 per cent in plasma, 90 per cent in liver, 79·8 per cent in brain and 86·3 per cent in muscle. M1appeared to be the major metabolite followed by eseroline. The results showed extremely low concentrations of Phy (200 times less in plasma and 350 times less in brain) after oral administration compared to our previous

ISSN:0142-2782    

DOI:10.1002/bdd.2510100208

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractA study was performed in 24 healthy male subjects to establish that two suspension formulations of cefixime were bioequivalent to each other and to a reference oral solution. A single 400mg oral dose of the drug was given in a randomized three‐way crossover design as two suspensions (a research suspension (RS) used during clinical trials and a suspension intended for marketing (MS)) and a reference oral solution (SOL). Each dose was separated from the other by a 3‐day washout period. Mean peak serum concentrations (Cmax) were 4·67, 4·10, and 4·27 μg ml−1after the MS, RS, and SOL, respectively. Although comparison (ANOVA) of the mean pharmacokinetic parameters for cefixime found significant differences (p0·05) were found in either the elimination half‐life or renal clearance of unchanged drug. Overall, with a 98 per cent power to detect a 20 per cent difference in AUC0→∞or urinary recovery values between the formulations tested, the results show that the MS was bioequivalent to the RS and that both suspensions were bioeq

ISSN:0142-2782    

DOI:10.1002/bdd.2510100209

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractIn a multiple dose cross‐over experiment in 12 healthy male adults the bioavailability and sustained release characteristics of new once daily BY912 400 mg theophylline capsules (= B, Byk Gulden Research Laboratories, FRG) were studied using Theo‐24® capsules (= T, Searle&Co., USA) as reference.Both products were given once daily for a period of 7 days as an 800 mg theophylline dose at 8 am, half an hour after a standardized breakfast.Theophylline concentrations in plasma were measured on days 1, 6, and 7 using highperformance liquid chromatography.Significantly better sustained release characteristics, resulting in longer plateau time (t75%, 11·6 vs 9·2 h on day 6 and 13·1 vs 8·8 h on day 7) and smaller per cent peak‐trough fluctuation in the steady state (per cent PTF, 80 vs 103 per cent on day 6 and 66 vs 100 per cent on day 7), were found for B in comparison with T.The extent of absorption on both days, however, was smaller for B compared with T (relative bioavailability 84 per cent and 81 per cent, respectively).In conclusion, the absorption of theophylline from B resulted in a more extended shape of the plateau phase, indicating better sustained release characteristics. The extent of absorption, however, over the dosing intervals was more compl

ISSN:0142-2782    

DOI:10.1002/bdd.2510100210

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractAn aqueous solution of 0·15 per cent benzydamine hydrochloride, a non‐steroidal anti‐inflammatory drug, was applied to the rabbit eye. Following topical application to the cornea, the drug was soon detected in the aqueous fluid of the treated eye, whereas the plasma levels were negligible. The possibility that benzydamine can inhibit inflammatory processes in the eye without the risk of side‐effects is dis

ISSN:0142-2782    

DOI:10.1002/bdd.2510100211

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510100202

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY