摘要:

Clinical Pharmacology and Therapeutics(1993)53, 617–621; doi:10.1038/clpt.1993.

ISSN:0009-9236    

DOI:10.1038/clpt.1993.81

年代:1993

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1993)53, 622–629; doi:10.1038/clpt.1993.

ISSN:0009-9236    

DOI:10.1038/clpt.1993.82

年代:1993

数据来源: WILEY

摘要:

Terfenadine is rapidly and nearly completely biotransformed during a first pass to an active acid metabolite. Accumulation of unmetabolized terfenadine has been associated with altered cardiac repolarization. Drug‐drug interactions resulting in the accumulation of terfenadine have been reported for ketoconazole and erythromycin. Six subjects were given the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral fluconazole (200 mg once daily). The mean metabolite area under the concentration‐time curve increased by 34% and the time to maximum concentration of the metabolite was delayed from 2.3 to 4 hours by concurrent fluconazole. Unmetabolized terfenadine was not present in any subject, and cardiac repolarization was not significantly changed from baseline during any phase of the study. We conclude that a pharmacokinetic interaction between terfenadine and fluconazole exists; however, the absence of accumulation of parent terfenadine in plasma suggests that a clinically significant interaction is unlikely.Clinical Pharmacology and Therapeutics(1993)53, 630–636; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1993.83

年代:1993

数据来源: WILEY

摘要:

Grapefruit juice produces a marked and variable increase in felodipine bioavailability. The pharmacokinetics of felodipine and its single primary oxidative metabolite, dehydrofelodipine, were studied after drug administration with 200 ml water, grapefruit juice, or naringin in water at the same concentration as the juice in a randomized crossover trial of nine healthy men. With grapefruit juice, mean ± SEM felodipine area under the plasma concentration‐time curve (AUC) and peak plasma concentration (Cmax) were 206% ± 23% (range, 123% to 330%,p<0.01) and 170% ± 24% (range, 127% to 310%,p<0.02), respectively, compared with water. Dehydrofelodipine/felodipine ratios for AUC (1.5 ± 0.2 versus 2.2 ± 0.2,p<0.001) and felodipine Cmax(1.5 ± 0.2 versus 2.2 ± 0.2,p<0.001) were reduced, consistent with inhibition of presystemic felodipine metabolism. Intersubject changes in felodipine and dehydrofelodipine AUC supported inhibition of both primary and secondary metabolic steps as a mechanism. The interaction could not be predicted from baseline pharmacokinetics with water and did not result in more consistent bioavailability among individuals. Naringin solution produced much less of an interaction, showing that other factors were important.Clinical Pharmacology and Therapeutics(1993)53, 637–642; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1993.84

年代:1993

数据来源: WILEY

摘要:

Disulfiram and its reduced metabolite diethyldithiocarbamate have been identified previously as selective mechanism‐based inhibitors of human liver microsomal cytochrome P450 2E1 in vitro. In animals, a single oral dose of disulfiram has been shown to produce a rapid and selective inactivation of hepatic P450 2E1 content and catalytic activity in vivo. This investigation explored the efficacy of single dose disulfiram as an inhibitor of human P450 2E1 activity in vivo. Clinical P450 2E1 activity was assessed by the 6‐hydroxylation of chlorzoxazone, a metabolic pathway catalyzed selectively by P450 2E1. Six healthy volunteers received 750 mg oral chlorzoxazone on two occasions in a crossover design, 10 hours after 500 mg oral disulfiram, or after no pretreatment (control subjects). Disulfiram pretreatment markedly decreased chlorzoxazone elimination clearance to 15% of control values (from 3.28 ± 1.40 to 0.49 ± 0.07 ml/kg/min,p<0.005), prolonged the elimination half‐life (from 0.92 ± 0.32 to 5.1 ± 0.9 hours,p<0.001), and caused a twofold increase in peak plasma chlorzoxazone concentrations (20.6 ± 9.9 versus 38.7 ± 10.3 µg/ml,p<0.001). Disulfiram also profoundly decreased the formation clearance of 6‐hydroxychlorzoxazone, from 2.30 ± 0.93 to 0.17 ± 0.05 ml/kg/min (p<0.005). These findings show that a single dose of disulfiram significantly diminishes the activity of human P450 2E1 in vivo. The efficacy of single‐dose disulfiram as an inhibitor of human P450 2E1 suggests that this modality for manipulating clinical P450 2E1 activity may provide a useful probe for delineating P450 2E1 participation in human drug biotransformation or for the treatment of poisoning by P450 2E1‐activated toxins.Clinical Pharmacology and Therapeutics(1993)53, 643–650; d

ISSN:0009-9236    

DOI:10.1038/clpt.1993.85

年代:1993

数据来源: WILEY

摘要:

Dosage adjustments of cyclosporine are confounded with an unexpected degree of variability, thus invalidating a direct proportionality between the oral dose rate and the steady‐state concentration. In 1033 observations of dose rate and average steady‐state concentration collected during therapeutic monitoring (area under the curve method) in 134 adult kidney transplant patients, a population pharmacokinetic analysis showed that a Michaelis‐Menten model fitted the data better than a linear clearance model. It was further shown that the Michaelis‐Menten constant (Km) parameter of the Michaelis‐Menten model (the average steady‐state concentration at half‐maximal dose rate) increased during the first 4 months after transplantation whereas the maximal dose rate of the Michaelis‐Menten model (Vmax) remained constant. The following parameters with interindividual variation in parenthesis were estimated: Vmax= 852 mg/24 hr (43%) and Kmat 114 days after transplantation = 349 ng/ml (117%). An algorithm was derived from this population model that guides the clinician during the adjustment of oral cyclosporine dose rates.Clinical Pharmacology and Therapeutics(1993)53, 651–660; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1993.86

年代:1993

数据来源: WILEY

摘要:

Amrinone‐associated thrombocytopenia is thought to result from nonimmune‐mediated peripheral platelet destruction. Platelet destruction may be a concentration‐dependent toxic effect of amrinone or its principal metaboliteN‐acetylamrinone. Eighteen children receiving amrinone after heart surgery were prospectively evaluated to correlate the pharmacokinetics of amrinone andN‐acetylamrinone with thrombocytopenia. Amrinone andN‐acetylamrinone plasma concentrations were determined by HPLC during loading, infusion, and terminal elimination, with concurrent monitoring of platelet counts. Thrombocytopenia developed in eight patients (platelet count, 66 ± 17 x 109platelets/L [mean ± SD]). Peak and steady‐state amrinone plasma concentration, amrinone total dose, duration of amrinone exposure, and amrinone area under curve (AUC) were similar between patients with and without thrombocytopenia.N‐Acetylamrinone peak concentration, steady‐state concentration,N‐acetylamrinone AUC, and ratio ofN‐acetylamrinone to amrinone were greater in patients with thrombocytopenia. This association suggests thatN‐acetylamrinone, and not amrinone, may be the mediator of thrombocytopenia in children receiving amrinone.Clinical Pharmacology and Therapeutics(1993)53, 661–6

ISSN:0009-9236    

DOI:10.1038/clpt.1993.87

年代:1993

数据来源: WILEY

摘要:

Enprostil, a synthetic prostaglandin E2analog, has been shown to decrease gastric acid secretion and plasma gastrin levels during short‐term treatment. However, effects of prolonged treatment with enprostil on these parameters in humans are unknown. We have studied the effects of 35 µg enprostil twice daily on 24‐hour intragastric pH, basal gastrin, and meal‐stimulated gastrin release in 10 healthy volunteers. Enprostil, 35 µg, was ingested twice daily for 4 weeks. Subjects were studied on day 0 (preentry) and days 1 and 29, when enprostil was taken 30 minutes before the first and third standard test meals at 9 AM and 5 PM. Enprostil significantly increased 24‐hour median pH (p<0.02) on day 1 but not on day 29. Enprostil had no significant effect on basal gastrin levels compared with placebo. However, on day 1, but not on day 29, postprandial gastrin levels were significantly lower compared with preentry (p<0.05). On day 29 postprandial gastrin levels after the second standard test meal were significantly higher compared with preentry data (p<0.05). In conclusion, 35 µg enprostil twice daily reduced gastric acidity and serum gastrin levels on the first day of treatment, but this effect attenuated and even transiently reversed during a 4‐week treatment period.Clinical Pharmacology and Therapeutics(1993)53, 668–674; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1993.88

年代:1993

数据来源: WILEY

摘要:

This study investigated the effects of isamoltane on the changes induced by cumulative doses of inhaled albuterol (salbutamol) on bronchomotor tone, skeletal muscle, circulatory system, and metabolism after single (day 1) and multiple dosing (day 7) in 15 healthy subjects. The volunteers were given placebo, 4 mg isamoltane, 10 mg isamoltane, or 20 mg propranolol over a 7‐day period in a randomized, double‐blind, crossover design. The greatest attenuation in albuterol‐induced β‐adrenergic receptor responses occurred with propranolol. The median provocative dose of albuterol causing a 50% increase in specific airway conductance was 337 and 315 µg (day 1 and day 7, respectively) for placebo, 336 and 322 µg for 4 mg isamoltane, 344 and 389 µg for 10 mg isamoltane, and 667 and 652 µg for propranolol. The provocative dose of albuterol producing a 35% increase in tremor was 464 and 539 µg (day 1 and day 7, respectively) for placebo, 1122 and 1270 µg for 4 mg isamoltane, 1612 and>1612 µg for 10 mg isamoltane, and>1612 and>1612 µg for propranolol. On day 5 of each period an exercise test was performed. Propranolol reduced exercise heart rate by 11% (compared with placebo), 10 mg isamoltane reduced heart rate by 5%, and 4 mg isamoltane reduced heart rate by 1%. In conclusion, low‐dose isamoltane caused measurable systemic effects on both β2‐ and β1‐adrenergic receptors, and the dose‐dependent blockade on β2‐receptors of skeletal muscle was more clear than the attenuation of exercise heart rate.Clinical Pharmacology and Therapeutics(1993)53, 675

ISSN:0009-9236    

DOI:10.1038/clpt.1993.89

年代:1993

数据来源: WILEY

摘要:

This study was undertaken to determine if a computerized pharmacokinetic program for adjusting theophylline infusion rates could attain a goal serum theophylline level more accurately than physician‐derived adjustments and what clinical impact this would have. Thirty‐five patients with diagnoses of asthma or chronic obstructive pulmonary disease were randomized to a control group (empiric) or experimental group (kinetic) after initial theophylline levels were drawn from each group. After second levels were drawn, patients in the kinetic group had their infusion rates adjusted by the computerized pharmacokinetic program to achieve a level of 15 mg/L, whereas patients in the empiric group had their infusions adjusted empirically by the primary care physicians to achieve a serum theophylline level of 15 mg/L. A final theophylline level was obtained just before the infusion was discontinued. The kinetic group was closer to the goal level of 15 mg/L than the empiric group, but this was not statistically significant (14.8 ± 4.4 versus 12.6 ± 4.1;p>0.05). The total number of days that patients were receiving intravenous theophylline was slightly longer for the kinetic group (4.1 ± 3.3 versus 3.2 ± 1.5;p>0.05) as was the total number of hospital days, but neither of these were statistically significant (11.4 ± 21.6 versus 8.8 ± 15.4 days;p>0.05). There were no differences between the two groups in the number of subtherapeutic or toxic levels, and there were no significant differences in arterial blood gas measurements. We were unable to show in this study any clinical advantage to adjusting the dosage of a theophylline infusion by a computerized pharmacokinetic program compared with adjustments made empirically by a physician.Clinical Pharmacology and Therapeutics(1993)53, 684–690; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1993.90

年代:1993

数据来源: WILEY