摘要:

Muzolimine (60 mg, administered orally) was administered to eight healthy volunteers, under conditions of altered fluid load, to elucidate its renal site of action. The duration of action and the effect of probenecid pretreatment on muzolimine response was also investigated. Muzolimine had a rapid onset of action, with the diuresis complete within 4 hours after dosing. At peak natriuresis, under hydrated conditions, fractional excretion of free water remained unaltered (9.72% ± 0.59% versus 9.07% ± 0.44%; difference not significant) but was accompanied by a significant increase in the delivery of sodium out of the proximal tubule, as measured by fractional excretion of lithium (22% ± 2% to 31% ± 1%;p<0.01). The fraction of sodium reabsorbed in the distal tubule also decreased from 94% ± 1% to 67% ± 1% (p<0.001) of the delivered load. The fractional reabsorption of free water during hydrope‐nia decreased after muzolimine (5.63% ± 0.26% to 2.00% ± 0.81%;p<0.05). Pretreatment with probenecid resulted in a prominent decrease in urinary sodium excretion (246 ± 25 mmol/24 hr for muzolimine alone; 161 ± 24 mmol/24 hr for muzolimine and probenecid;p<0.01). These findings suggest that muzolimine has a major site of action in the medullary portion of the thick ascending limb of Henle with additional inhibitory activity on the proximal tubule. It is likely that the active secretion of one or more of the acidic metabolites of muzolimine, by way of the probenecid sensitive organic acid pathway, is responsible for mediating the renal actions this basic drug.Clinical Pharmacology and Therapeutics(1991)50,564–572; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1991.182

年代:1991

数据来源: WILEY

摘要:

Patients receiving the investigational antineoplastic agent amonafide underwent prospective determination of acetylator phenotype with use of caffeine as a test drug. Fast acetylators of caffeine had significantly greater toxicity (myelosuppression) after amonafide treatment than slow acetylators, presumably because of greater conversion of amonafide to the active acetylated metabolite. Furthermore, the estimated area under the plasma concentration—time curve of amonafide was significantly greater in the fast acetylators, indicating that the total plasma clearance was paradoxically lower in this group. It is hypothesized that this paradox is attributable to competition for oxidation of amonafide by its acetylated metabolite (parallel pathway interaction). Pretreatment white blood count and patient age were also independent predictors of leukopenia. In addition, it was noted that the ratio of actual to ideal body weight was significantly higher in the fast acetylators. Studies are in progress to determine the optimal amonafide dose in both acetylator subgroups.Clinical Pharmacology and Therapeutics(1991)50,573–579; doi:10.1038/clpt.1991

ISSN:0009-9236    

DOI:10.1038/clpt.1991.183

年代:1991

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1991)50,580–586; doi:10.1038/clpt.1991.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.184

年代:1991

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1991)50,587; doi:10.1038/clpt.1991.185

ISSN:0009-9236    

DOI:10.1038/clpt.1991.185

年代:1991

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1991)50,588–592; doi:10.1038/clpt.1991.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.186

年代:1991

数据来源: WILEY