摘要:

Clinical Pharmacology and Therapeutics(1991)49,229–233; doi:10.1038/clpt.1991.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.21

年代:1991

数据来源: WILEY

摘要:

The pharmacokinetics of thioridazine and its metabolites were studied in 19 healthy male subjects: 6 slow and 13 rapid hydroxylators of debrisoquin. The subjects received a single 25 mg oral dose of thioridazine, and blood samples were collected during 48 hours. Concentrations of thioridazine and metabolites in serum were measured by HPLC. Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4‐fold higher Cmaxand a 4.5‐fold larger AUC(0‐∞) associated with a twofold longer half‐life compared with that of rapid hydroxylators. The side‐chain sulphoxide (mesoridazine) and sulphone (sulphoridazine), which are active metabolites, appeared more slowly in serum and had lower Cmaxvalues, but comparable AUC. The thioridazine ring‐sulphoxide attained higher Cmaxand 3.3‐fold higher AUC in slow hydroxylators than in rapid hydroxylators of debrisoquin. Thus the formation of mesoridazine from thioridazine and the 4‐hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thioridazine ring‐sulphoxide is probably formed mainly by another enzyme.Clinical Pharmacology and Therapeutics(1991)49,234–240; do

ISSN:0009-9236    

DOI:10.1038/clpt.1991.22

年代:1991

数据来源: WILEY

摘要:

Twelve patients with cirrhosis (seven mild and five severe) were administered intravenous and oral furosemide in random order to assess its absorption and disposition. Total serum clearance (113 ± 49 ml/min), volume of distribution (11.9 ± 4.5 L), and elimination half‐life (166 ± 149 minutes) were similar to those reported previously in both healthy control subjects and patients with cirrhosis. Bio‐availability of 58% ± 17% (range, 37% to 82%) was comparable to that of previous studies, and there was no difference between patients with mild and those with severe cirrhosis. In 9 of 12 patients the mean absorption time was longer than the mean residence time determined after intravenous administration (mean for all patients, 203 ± 86 versus 134 ±101 minutes;p<0.05), indicating that furosemide followed a “flip‐flop” model in these patients. In all patients the mean absorption time was prolonged relative to normal subjects irrespective of the presence of edema. As such, the slower absorption of furosemide in edematous states, such as congestive heart failure and cirrhosis, does not appear to be a consequence of edema per se. Moreover, because similar changes occur in patients with congestive heart failure, it seems that diseases with diverse pathophysiology can slow furosemide absorption.Clinical Pharmacology and Therapeutics(1991)49,241–247; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1991.23

年代:1991

数据来源: WILEY

摘要:

During this open, two‐period crossover study in eight healthy volunteers, 1200 mg anhydrous theophylline was administered as a two‐stage infusion during 24 hours on day 6. During one of the 8‐day periods, 300 mg caffeine, t.i.d., was administered orally. After the start of the theophylline infusion, plasma concentrations of theophylline and caffeine and urinary excretion of theophylline and four metabolites were determined frequently during 60 hours. With caffeine administration theophylline steady‐state concentration and area under the curve increased by 23% and 40%, respectively, whereas the volume of distribution at steady state seemed unchanged. The cumulative urinary excretion of 1‐methyluric acid and 1‐methylxanthine did not reach a plateau, suggesting a capacity‐limiting factor in their formation. Notwithstanding the mutual interference of theophylline and caffeine metabolism, the reduction in apparent total body clearance and elimination rate constant of theophylline by 29% and 31%, respectively, indicated a pronounced influence of concomitant administration of realistic amounts of caffeine.Clinical Pharmacology and Therapeutics(1991)49,248–255; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.24

年代:1991

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1991)49,255; doi:10.1038/clpt.1991.25

ISSN:0009-9236    

DOI:10.1038/clpt.1991.25

年代:1991

数据来源: WILEY

摘要:

The interaction between digoxin and verapamil was studied in six patients (mean age ± SD, 61 ± 5 years) with chronic atrial fibrillation. The effects of adding verapamil (240 mg/day) on steady‐state plasma concentrations and renal and biliary clearances of digoxin were studied in a crossover manner. The biliary clearance of digoxin was determined by a duodenal perfusion technique. Verapamil induced a 44% increase in steady‐state plasma concentrations of digoxin, from 0.80 ± 0.24 to 1.15 ± 0.40 nmol/L(p<0.01). The biliary clearance of digoxin decreased by 43%, from 187 ± 89 to 101 ± 55 ml/min(p<0.05), in the presence of verapamil, whereas the renal clearance was unaffected (153 ±31 versus 173 ± 51 ml/min; difference not significant). Our results indicate that the main inhibitory effect of verapamil on digoxin elimination is on the biliary route.Clinical Pharmacology and Therapeutics(1991)49,256–262; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1991.26

年代:1991

数据来源: WILEY

摘要:

The pharmacokinetics of cefpiramide, a new cephalosporin, were investigated after a single 1 gm intravenous injection in 11 patients with alcoholic cirrhosis and compared with those of 11 healthy subjects. In patients with cirrhosis the plasma elimination half‐life was three times longer than that in normal subjects. The total plasma clearance was decreased significantly(p<0.001): 12.3 ± 6.5 ml/min in patients and 25.6 ± 4.6 ml/min in healthy volunteers, respectively. The urinary excretion of unchanged drug (percent of intravenous dose) for patients (69.8% ± 29.9%) was statistically higher(p<0.01) than that for subjects (16.2% ± 3.9%). The renal elimination became increasingly important with hepatic impairment. Protein binding of cefpiramide was reduced significantly in the group with cirrhosis. The average unbound fraction was 10.4% ± 9.5% in patients with cirrhosis and 1.9% ± 0.3% in normal subjects(p<0.01). Because the rate of elimination from plasma in patients is slower, the dosage regimen of cefpiramide would probably be modified in cirrhosis.Clinical Pharmacology and Therapeutics(1991)49,263–269; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1991.27

年代:1991

数据来源: WILEY

摘要:

The stable isotope‐labeled compound 3', 3'‐dideuteronicotine was used to investigate the disposition kinetics of nicotine in smokers, the systemic absorption of nicotine from cigarette smoke, and the bioavailability of nicotine ingested as oral capsules. Blood levels of labeled nicotine could be measured for 9 hours after a 30‐minute intravenous infusion. Analysis of disposition kinetics in 10 healthy men revealed a multiexponential decline after the end of an infusion, with an elimination half‐life averaging 203 minutes. This half‐life was longer than that previously reported, indicating the presence of a shallow elimination phase. Plasma clearance averaged 14.6 ml/min/kg. The average intake of nicotine per cigarette was 2.29 mg. A cigarette smoke‐monitoring system that directly measured particulate matter in smoke was evaluated in these subjects. Total particulate matter, number of puffs on the cigarette, total puff volume, and time of puffing correlated with the intake of nicotine from smoking. The oral bioavailability of nicotine averaged 44%. This bioavailability is higher than expected based on the systemic clearance of nicotine and suggests that there may be significant extrahepatic metabolism of nicotine.Clinical Pharmacology and Therapeutics(1991)49,270–277; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1991.28

年代:1991

数据来源: WILEY

摘要:

To examine the effects of the two newest monophasic oral contraceptives on liver microsomal drug metabolism, plasma kinetics and urinary metabolite excretion of antipyrine, a model substrate for liver mi‐crosomes, were evaluated. Plasma lipid and lipoprotein levels, and in particular the high‐density lipoprotein subfractions, were also monitored in view of their apparent regulation by a P450‐dependent system. Ten healthy volunteers were treated with each contraceptive for a period of 3 months in a crossover trial. Both contraceptives significantly reduced antipyrine clearance by 34.6% (gestodene) and 43.3% (desogestrel) by impairing the oxidative metabolism, particularly to the 4‐hydroxy and 3‐hydroxymethyl metabolites, with little difference between the two associations. In addition, with both a comparable highly significant rise of plasma triglycéride levels, apolipoproteins A‐I and A‐II and the high‐density lipoprotein‐3 subfraction was observed. Treatment with these new monophasic contraceptives may reduce the metabolism of concomitantly given drugs undergoing oxidative transformations.Clinical Pharmacology and Therapeutics(1991)49,278–284; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1991.29

年代:1991

数据来源: WILEY

摘要:

Fenoldopam mesylate stimulates adenyl cydase in porcine ocular trabecular meshwork and raises intraocular pressure in humans. To clarify whether this results from direct activation of the dopamine‐1 receptor or indirectly from baroreflex sympathetic stimulation after blood pressure reduction, intraocular pressure was measured in 14 patients with accelerated/malignant hypertension, randomized between intravenous fenoldopam or sodium nitroprusside. Intraocular pressure was measured with a Perkins tonometer, before and at the twentieth minute of each dose increment. In seven patients with a mean blood pressure of 232/131 mm Hg treated with fenoldopam, intraocular pressure increased in a dose‐dependent fashion, from 16 ± 1 to 20 ± 2 mm Hg(p<0.005). In contrast, seven patients with a mean blood pressure of 225/134 mm Hg treated with sodium nitroprusside exhibited no change in intraocular pressure (15 ± 1 versus 14 ± 1 mm Hg) despite similar blood pressure reduction. Increases in heart rate were not significantly different. Rates of urinary excretion of norepinephrine plus epinephrine increased significantly relative to baseline(p<0.05) but were not different between groups. These data suggest that the increase in intraocular pressure with fenoldopam results from specific activation of the dopamine‐1 receptor and is not caused by baroreflex sympathetic stimulation. Because dopamine‐1 receptors may modulate intraocular pressure, dopamine‐1 receptor blockers might be useful therapy for glaucoma.Clinical Pharmacology and Therapeutics(1991)49,285–293; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.30

年代:1991

数据来源: WILEY