摘要:

Interaction between ketoconazole, itraconazole, and midazolam was investigated in a double‐blind, randomized crossover study of three phases at intervals of 4 weeks. Nine volunteers were given either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo orally once daily for 4 days. On day 4, the subjects ingested 7.5 mg midazolam. Plasma samples were collected and psychomotor performance was measured. Both ketoconazole and itraconazole increased the area under the midazolam concentration‐time curve from 10 to 15 times(p<0.001) and mean peak concentrations three to four times(p<0.001) compared with the placebo phase. In psychomotor tests (e.g., the Digit Symbol Substitution Test), the interaction was statistically significant(p<0.05) until at least 6 hours after drug administration. Inhibition of the cytochrome P450IIIA by ketoconazole and itraconazole may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving ketoconazole and itraconazole should be avoided.Clinical Pharmacology and Therapeutics(1994)55,481–485; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.60

年代:1994

数据来源: WILEY

摘要:

ObjectiveOmeprazole is an effective drug for treating active peptic ulcer, whereas tripotassium dicitrato bismuthate can prevent ulcer relapse ifHelicobacter pyloriis eradicated. Because both drugs will be given concomitantly, drug interactions have to be considered, especially since absorption of bismuth may be dependent on intragastric pH, which will be elevated by omeprazole.MethodsIn a placebo‐controlled crossover study, six healthy volunteers received daily oral doses of 40 mg omeprazole for 1 week and a single oral dose of 240 mg triptoassium dicitrato bismuthate. Plasma concentration‐time profiles (AUC) and urinary excretion (Ae) of bismuth were measured by atomic absorption spectrophotometry and plasma levels of omeprazole by HPLC. In addition, intragastric pH values were monitored for 8 hours.ResultsAs expected, control mean pH values (2.1) were evaluated to 4.7 by omeprazole(p= 0.001), which was eliminated with a half‐life of 1.3 ± 0.7 hours (mean ± SD) and an oral clearance of 387 ± 221 ml/min. The increase of intragastric pH was related to the AUC of omeprazole (r = 0.89;p= 0.017). Omeprazole increased absorption of bismuth because AUC and Ae were higher(p≤ 0.05) during omeprazole treatment (172 ± 158 μg/L · hr and 1.9 ± 2.0 mg/8 hr, respectively) compared with placebo (46 ± 33 μg/L · hr and 0.27 ± 0.28 mg/8 hr, respectively). A significant correlation(r= 0.85;p= 0.038) could be observed between intragastric pH differences and Ae values.ConclusionsOmeprazole caused an increase of the systemic availability of bismuth from tripotassium dicitrato bismuthate. Whether this pharmacokinetic interaction between both drugs results in alterations ofH. pylorieradication or the toxic potential of bismuth remains to be elucidated by further clinical studies.Clinical Pharmacology and Therapeutics(1994)55,486–491; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1994.61

年代:1994

数据来源: WILEY

摘要:

Phenotypic trait values in 166 healthy white subjects (age range, 18 to 88 years) were determined for dapsoneN‐hydroxylation, dapsoneN‐acetylation, debrisoquin 4‐hydroxylation, andS‐mephenytoin 4'‐hydroxylation after single oral dose administration of the probe drugs dapsone (100 mg), debrisoquin (10 mg), and mephenytoin (100 mg). No associations or evidence of cosegregation were found between the individual routes of metabolism. DapsoneN‐hydroxylation exhibited a unimodal distribution, with marked (tenfold) intersubject variability, and aging was associated with reducedN‐oxidation. However, the other measured routes of metabolism were age independent, but intersubject variability in all of the trait measurements increased with age. In subjects younger than 50 years,S‐mephenytoin 4'‐hydroxyla‐tion was modestly (34%) less in men than in women. In contrast, dapsoneN‐acetylation, dapsoneN‐hydroxylation, and debrisoquin 4‐hydroxylation were not influenced by gender. Previous smoking habit and alcohol consumption were not associated with a difference in any of the four routes of metabolism. Accordingly, the measured phenotypic traits of drug oxidation andN‐acetylation appear to be quite robust in regard to some common demographic variabilities present in population studies, with the exception of dapsoneN‐hydroxylase, which is affected by aging.Clinical Pharmacology and Therapeutics(1994)55,492

ISSN:0009-9236    

DOI:10.1038/clpt.1994.62

年代:1994

数据来源: WILEY

摘要:

A pharmacokinetic study of folic acid and its metabolites was conducted to provide a basis to consider folic acid as a therapeutic alternative to leucovorin. Leucovorin has been used in various folate antagonist rescue regimens and to modulate fluorouracil activity in the treatment of solid tumors. Although leucovorin is typically administered intravenously in fluorouracil modulation therapy, limited oral administration trials have yielded equivalent responses. Because metabolites rather than leucovorin are the predominant circulating species after oral administration, these clinical results indicate that metabolites themselves can be modulating agents. Folk acid could be an attractive alternative to leucovorin provided it effectively elevates the same plasma metabolites. Hence, folk acid at doses of 25 and 125 mg/m2was administered orally and intravenously to normal volunteers. Plasma folk acid and its reduced folate metabolites were monitored over a 24‐hour period by use of a previously developed radioenzymatic method. The metabolites that accumulated—5‐methyltetrahydrofolate, 5,10‐methylenetetrahydrofolate, tetrahydrofolate, and 10‐formyltetrahydrofolate—were the same metabolites that were observed previously after leucovorin administration. Folk acid metabolites accumulated more slowly and persisted longer than leucovorin metabolites, which can be attributed to slower metabolism of the fully oxidized vitamin. Based on these results, it is concluded that folk acid could be an attractive therapeutic alternative to leucovorin for fluorouracil modulation.Clinical Pharmacology and Therapeutics(1994)55,501–508; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1994.63

年代:1994

数据来源: WILEY

摘要:

Pharmacokinetics and pharmacodynamics ofS‐verapamil were studied in 25 healthy nonsmoking women ranging in age from 23 to 33 years (young) and from 63 to 79 years (elderly) after 15‐minute intravenous infusions of 0.10 to 0.11 mg/kg.S‐Verapamil clearance decreased in an age‐related manner (15.7 ± 3.5 ml/min/kg in young women versus 12 ± 1.5 ml/min/kg in elderly women;p<0.0004) and elimination half‐life values increased in an age‐related manner from 347 ± 97 minutes in young women to 453 ±153 minutes in elderly women(p<0.05). Neither volume of distribution beta, steady‐state volume of distribution, nor protein binding were altered by age.S‐Verapamil decreased blood pressure(p<0.0001), increased PR intervals during sinus rhythm(p<0.0001), and transiently increased heart rate(p<0.0001) in both young and elderly subjects. Age‐related differences in responses were seen for mean(p<0.03) and systolic blood pressure(p<0.002) (greater decreases in the elderly), heart rate (less increase in the elderly;p<0.0001), and PR intervals during sinus rhythm (less prolongation in the elderly;p<0.0001). In summary, aging altersS‐verapamil pharmacokinetics and pharmacodynamics in women.Clinical Pharmacology and Therapeutics(1994)55,509–517

ISSN:0009-9236    

DOI:10.1038/clpt.1994.64

年代:1994

数据来源: WILEY

摘要:

The influence of the sparteine and theS‐mephenytoin oxidation polymorphisms on the kinetics of clomipramine were investigated in 25 healthy volunteers: 10 extensive metabolizers of sparteine and mephenytoin (EMs/EMm), nine poor metabolizers of sparteine and extensive metabolizers of mephenytoin (PMs/EMm), five extensive metabolizers of sparteine and poor metabolizers of mephenytoin (EMs/PMm), and one poor metabolizer of sparteine and mephenytoin (PMs/PMm). A single oral dose of 100 mg clomipramine hydrochloride was given to each subject after an overnight fast. Serum and urine levels of clomipramine and its metabolites were monitored after 1, 2, 3, 4, 6, 8, 11, 14, 24, 36, 48, and 96 hours. Additional serum was monitored after 6, 9, 12, and 15 days in the poor metabolizers. 2‐Hydroxyclomi‐pramine was undetectable in most subjects before enzymatic hydrolysis of serum and urine. The total median clearance of clomipramine was 99 L · hr−1(range, 68 to 210) in the EMs/EMmsubjects, 56 L · hr−1(range, 37 to 183) in the PMs/EMmsubjects, 66 L · hr−1(range, 37 to 89) in the EMs/PMmsubjects, and 43 L · hr−1in the PMs/EMmsubject. It was significantly lower in PMs/EMmand EMs/PMmsubjects compared with EMs/EMmsubjects(p= 0.006 and 0.028, respectively; Mann‐Whitney). In addition, the formation clearance of 2‐hydroxyclomipramine and the hydroxylation indexes were significantly lower in PMs/EMmsubjects, as was the demethylation index in EMs/PMmsubjects compared with EMs/EMmsubjects. Our data thus provide evidence that the 2‐ and 8‐hydroxylation of clomipramine are catalyzed by CYP2D6 and that theN‐demethylation is catalyzed in part by CYP2C.Clinical Pharmacology and Therapeutics(1994)55,518

ISSN:0009-9236    

DOI:10.1038/clpt.1994.65

年代:1994

数据来源: WILEY

摘要:

ObjectiveTo determine whether the activity of cytochrome P450 isoforms involved in the metabolism of(R)‐warfarin is enhanced in cystic fibrosis.DesignSix adult subjects with cystic fibrosis and six healthy control subjects, matched by age and sex, were administered(R)‐warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 192 hours. The concentration of(R)‐warfarin in plasma and the concentration of(R)‐warfarin and its metabolites in urine were determined by HPLC and GC/MS, respectively. Plasma protein binding of(R)‐warfarin was measured by ultrafiltration.ResultsThe unbound plasma clearance of(R)‐warfarin was not significantly(p>0.05) different between the cystic fibrosis and the control groups (cystic fibrosis, 997 ± 483 ml/hr/kg; control, 788 ± 219 ml/hr/kg). The unbound metabolic clearances of(R)‐warfarin to its oxidative metabolites—6‐hy‐droxywarfarin, 7‐hydroxywarfarin, 8‐hydroxywarfarin, and 10‐hydroxywarfarin (mediated by P450 3A4)—were also similar(p>0.05) in the two groups(6‐hydroxywarfarin: cystic fibrosis: 124.2 ± 72.8 ml/hr/kg, control: 99.4 ± 37.3 ml/hr/kg;7‐hydroxywarfarin: cystic fibrosis: 43.8 ± 32.2 ml/hr/kg, control: 34.5 ± 10.6 ml/hr/kg;8‐hydroxywarfarin: cystic fibrosis: 80.4 ± 85.4 ml/hr/kg, control: 69.5 ± 39.5 ml/hr/kg;10‐hydroxywafarin: cystic fibrosis: 4.38 ± 2.72 ml/hr/kg, control: 16.28 ± 13.71 ml/hr/kg).ConclusionThe in vivo activity of cytochrome P450 isoforms involved in the metabolism of(R)‐warfarin, including P450 3A4, is not enhanced in cystic fibrosis.Clinical Pharmacology and Therap

ISSN:0009-9236    

DOI:10.1038/clpt.1994.66

年代:1994

数据来源: WILEY

摘要:

ObjectiveTo study the pharmacodynamic effects of intravenous temazepam after different infusion rates to pseudo steady‐state concentrations.MethodsThis was a randomized, double‐blind, placebo‐controlled crossover study in an academic department of clinical pharmacology. Subjects were nine healthy volunteers. A computerized infusion pump was used to obtain target plasma concentrations of temazepam after 30 or 120 minutes and to maintain these levels for 2 hours. A vehicle inftision, similar to the 30‐minute (fast) infusion was used as a placebo control. Infusion schedules were based on data obtained from individual subjects after inftision of 0.4 mg/kg temazepam in 30 minutes. Target plasma concentrations were chosen to induce subhypnotic effects and averaged (± SD) 597 ± 123 ng/ml. Venous plasma concentrations of temazepam were measured by HPLC. Free fractions of temazepam were assessed at the start of the pseudo steady‐state concentration intervals. Electroencephalogram alpha and beta amplitudes, saccadic peak velocity, and saccadic latency were used as pharmacodynamic parameters.ResultsThe rate of change of plasma concentrations averaged 21 ± 4 ng/ml · min−1during fast infusion and 5 ± 1 ng/ml · min−1during slow infusion of temazepam. Average pseudo steady‐state concentrations were 639 ± 132 ng/ml after fast infusion and 629 ± 133 ng/ml after slow infusion. At the onset of pseudo steady‐state concentration intervals the average free fractions of temazepam were 44% (95% confidence interval, 19% to 61%) lower for slow than for fast infusions. Compared with the slow infusion, electroencephalogram beta amplitudes were significantly larger during the first 30 minutes of pseudo steady‐state concentration after fast infusion of temazepam. No significant differences were found for the other parameters. There was a slight decline of temazepam effects during the pseudo steady‐state concentration intervals for all parameters after the fast infusion and for saccadic peak velocity and saccadic latency after the slow infusion.ConclusionsThe pharmacodynamic effects of intravenous temazepam may depend partly on the rate of administration. Differences in pharmacodynamic effects after fast and slow infusions could be caused by changes in protein binding over time.Clinical Pharmacology and Therapeutics(1994)55,535

ISSN:0009-9236    

DOI:10.1038/clpt.1994.67

年代:1994

数据来源: WILEY

摘要:

ObjectiveTo evaluate the long‐term reproducibility of pharmacokinetic, pharmacodynamic, and concentration‐effect parameters after intravenous administration of temazepam.MethodsNine healthy volunteers were studied. Temazepam, 0.4 mg/kg, was infused intravenously for 30 minutes on two occasions 6 months apart. Venous plasma concentrations of temazepam were measured by HPLC in samples obtained between 0 and 24 hours. Pharmacodynamic effects were evaluated up to 8 hours for saccadic peak velocity and electroencephalogram (EEG) beta amplitudes. Subjects' state and trait anxiety were assessed by use of the Spielberger anxiety inventory.ResultsSignificant correlations between occasions were found for area under the plasma concentration‐time curve (AUC) values(r= 0.91;p<0.01) but not for maximum concentration and half‐life. Significant correlations were also found for area under the effect‐time curve (AUEC) values of peak velocity (r = 0.88;p0.05). Significant differences between the slopes of concentration effect plots on different occasions were observed in two subjects' for EEG beta and in three subjects for peak velocity, with one subject showing a similar change for both parameters. Trait anxiety scores were higher on the first occasion (33 ± 7) than on the second occasion (29 ± 7;p<0.01). A negative correlation was found between trait anxiety scores and the slopes of concentration‐effect plots for peak velocity(r= ‐0.63;p<0.01).ConclusionsFor AUC and AUEC values the results indicate a reasonable long‐term reproducibility of differences between subjects in the pharmacokinetics and pharmacodynamics of temazepam. However, there were limitations to the predictive value of derived concentration‐effect parameters.Clinical Pharmacology and Therapeutics(1994)55,546–555; do

ISSN:0009-9236    

DOI:10.1038/clpt.1994.68

年代:1994

数据来源: WILEY

摘要:

ObjectivesTo show the subjective and cardiovascular effects of khat leaves having a standardized content of cathinone.BackgroundThe main effect of khat is an increase of energy and alertness. This effect is thought to be attributable to the phenylalkylamine cathinone, but no controlled clinical trials have been published.DesignThe design was balanced and double blind. Six drug‐naïve volunteers received a single dose of khat corresponding to 0.8 mg/kg body weight, as well as alkaloid‐free khat as a placebo. Psychologic effects were evaluated by the Addiction Research Center Inventory (ARCI) and visual analog scales. Physiologic measures were systolic blood pressure, diastolic blood pressure, and heart rate. Plasma concentrations of cathinone and its metabolites norephedrine and R,R‐(—) norpseudoephedrine were determined by HPLC.ResultsMaximal plasma concentrations of cathinone (127 ± 53 [SD] ng/ml) were attained after 127 ± 30 minutes. The area under the plasma concentration—time curve from 0 to 9 hours was 415 ± 207 ng/ml · hr, and the terminal elimination half‐life was 260 ± 102 minutes. An effect of khat was observed in the ARCI scales Abuse Potential(p<0.01), Motor Stimulation(p<0.02), Amphetamine‐Like Effect(p<0.005), and Stimulation‐Euphoria(p<0.005), as well as in the visual analog scales Excited‐Calm(p<0.001) and Energetic‐Lethargic(p<0.001).ConclusionsOur results provide objective evidence for the amphetamine‐like stimulatory effects of khat leaves. These effects were closely similar to those observed after cathinone, 0.5 mg/kg body weight, although peak plasma concentrations of cathinone after khat were delayed.Clinical Pharmacology and Therapeutics(1994)55,556

ISSN:0009-9236    

DOI:10.1038/clpt.1994.69

年代:1994

数据来源: WILEY