摘要:

AbstractThe pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4 and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax⋍2h) and an elimination half‐life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F⋍29 mL min−1;Vz/F⋍32L); urinary excretion was ∼9% of dose, corresponding to a renal clearance of only 3 mL min−1(a value consistent with the rate of glomerular filtration of unbound drug).In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of14C‐labelled reboxetine, appeared to be dominated by α1‐acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL−1(2.8–3.1% unbound with human plasma from three additional volunteers; 1.8–2.0% for 2gL−1orosomucoid α1‐acid glycoprotein, and 46.4–47.4% for 40 gL−1albumin), whilst the meanCmaxin the current study was much low

ISSN:0142-2782    

DOI:10.1002/bdd.2510160603

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractAmphotericin B (AmB) is widely used for the treatment of systemic mycoses. The current therapeutic regimens for this drug are complex and somewhat empirical, in part because of very limited information about the disposition kinetics of this agent. In this study, we examined the disposition kinetics of AmB as a function of dose and estimated clearance values using a steady state study design in an animal model. Groups of male Sprague‐Dawley rats were given diferent two‐step infusion regimens to achieve three different steady state concentrations (i.e., three different total infused doses). We observed no significant differences in systemic clearance among the three AmB doses studied. Similarly, only small differences were seen in volumes of distribution as a function of dose. However, renal clearance decreased significantly as the total infused dose was increased (0.76 ± 0.33, 0.86 ± 0.24, and 0.37 ± 0.04mL min−1kg−1for the lowmedium and high‐dose groups, respectively;p<0.05). Signs of renal impairment were observed in the high‐dose group, as documented by decreased creatinine clearance. Dose‐dependent renal clearance may have ben due either to nephrotoxicity associated with the high dose of AmB and/or to saturation of an active secretion process. Furthermore, clearance values estimated from steady state conditions were similar to those from time‐averaged values (based on the estimation of area under the plasma concentration‐time profile). This suggests that clearance calculations from time‐averaged concentrations provide reasonable estimates, since steady state plasma concentrations could be reliably determined. However, the possibility that a true tissue steady state condition was not achieved with our study design cannot be ruled out. Further investigation is necessary to identify the renal excretion mechanisms of AmB and to reach steady state tissue concentration to confirm the estimation

ISSN:0142-2782    

DOI:10.1002/bdd.2510160604

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe adherence of a sucralfate—tetracycline complex to gastric ulcers and to nearby nonulcer sites was determined in the rabbit antrum. Persistent gastric ulcers were produced by a previously described method. The presence of the complex was assessed 1 and 4 h after dosing. Drug adherence was determined by quantitation of aluminum in stomach wall biopsies. Significantly more aluminum adhered to ulcer sites than to nearby nonulcer sites. Adherence of the complex did not significantly decrease from 1 to 4 h. The complexation of tetracycline to sucralfate did not alter the selective adherence of sucralfte to gastric ulcers, providing a mechanism of ulcer site‐selective drug delivery in the treatment ofHelicobacter pylorigastric ulcer dise

ISSN:0142-2782    

DOI:10.1002/bdd.2510160605

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe influence of caffeine (60 mg) was studied on the pharmacokinetic characteristics of acetaminophen (500 mg single dose) in ten healthy male human volunteers in a complete cross‐over design. A high‐performance liquid chromatography (HPLC) method was used to analyse serum drug concentrations. Caffeine caused a highly significant (p<0.01) increase in AUC and AUMC, a significant (p<0.05) increase inCmax, and a significant (p<0.05) decrease in clearance (Cl/F) of acetaminophen. We conclude that caffeine taken in doses commonly available commercially or in a cup of coffee can significantly potentiate the therapeutic potential of acetaminophen in

ISSN:0142-2782    

DOI:10.1002/bdd.2510160606

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics and tissue distribution of M1–M4 were compared after intravenous (IV) administration of DA‐125, 25 mg kg−1, to BDF1mice (n= 5 at each sampling time) and subcutaneously implanted Lewis‐lung‐carcinoma‐bearing BDF1mice (n= 10 at each sampling time). The mean plasma concentrations of M1–M4 were not significantly different between the two groups of mice, and hence similar pharmacokinetic parameters for M1–M4 were obtained. The amount of M1 in the lung was significantly greater in the tumour‐bearing mice than in the control mice, resulting in a greater AUA, in the tumour‐bearing mice (18 600 against 8940 μg min g−1), andvice versain the liver (962 against 3840 μg min g−1). However, the corresponding values for other tissues were comparable between the control and tumour‐bearing mice. The amount of M1 was greatest in the lung for up to 2 h in the tumour‐bearing mice. M2 was the predominant metabolite among M1–M4 excreted in 24 h urine by both groups of mice; 8.36 and 10.7% of the IV dose were excreted in 24 h urine as M2–expressed in terms of DA‐125—by the control and tumour‐bearing mice, respectively. The amount of M1 in the tumour mass reached a meanCmaxof 3.75 μg g−1immediately after IV administration of DA‐125 to the tumour‐bearing mice, then declined very slowly to an amount that remained almost constant for up to 24 h. This suggested that M1 has high affinity for the subcutaneously implanted Lewis lung carcinoma. The antitumour activity, such as the increase in life span (ILS) and tumour growth inhibition (TGI) of DA‐125, 6–48 mg kg−1, and adriamycin (ADM), 3–18 mg kg−1, were also compared in subcutaneously implanted Lewis‐lung‐carcinoma‐bearing BDF1mice after four weekly IV administrations of the drugs on days 1, 8, 15, and 22 following tumour implantation. More than three out of six mice survived as tumour‐free for longer than 70 d at a DA‐125 dose range of 6–24 mg kg−1, but there were no tumour‐free mice at any dose of ADM. Assuming ILS values higher than 30% to be effective, DA‐125 doses ranging from 6 to 24 mg kg−1were effective in increas

ISSN:0142-2782    

DOI:10.1002/bdd.2510160607

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractAfter epidural administration of 15 mg 3, 6‐dinicotinoylmorphine (nicomorphine) in 10 patients undergoing pulmonary surgery, the parent compound was quickly metabolized into the metabolites 6‐mononicotinoylmorphine and morphine. The mean apparent half‐lives (±SD) of elimination were 10 min (0.165 h ± 0.053 h) for 3, 6‐dinicotinoylmorphine and 1.77 h ± 1.23 h for 6‐mononicotinoylmorphine. Morphine is subsequently metabolized into morphine‐3‐glucuronide, and morphine‐6‐glucuronide. The apparent half‐lives of morphine, morphine‐3‐glucuronide, and morphine‐6‐glucuronide are similar: 3.63 h ± 1.63 h, 4.10 h ± 0.57 h, and 4.20 h ± 1.64 h respectively. The possible glucuronide conjugate of 6‐mononicotinoylmorphine was not detected. The prodrug 3, 6‐dinicotinoylmorphine was biotransformed into three active compounds: 6‐mononicotinoylmorphin

ISSN:0142-2782    

DOI:10.1002/bdd.2510160608

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160609

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160610

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160611

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510160612

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY