摘要:

Clinical Pharmacology and Therapeutics(1994)56,237–241; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.130

年代:1994

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1994)56,242–243; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.132

年代:1994

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1994)56,244–247; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.133

年代:1994

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1994)56,248–252; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.134

年代:1994

数据来源: WILEY

摘要:

Interpatient differences in the kinetics of cyclosporine appear to result in part from interindividual differences in the catalytic activity of an enzyme termed P450 3A. We investigated the relationship between P450 3A activity, as measured by the erythromycin breath test (ERMBT), and the appropriate stable daily dose of cyclosporine as currently determined by physicians at our institution. The ERMBT was administered to kidney and heart allograft recipients who had attended at least two monthly clinic visits without having their daily cyclosporine dose changed. There was a significant positive correlation between the ERMBT result and the daily cyclosporine doses (in milligrams per kilogram) in both the heart (r= 0.68;p= 0.04;n= 9) and kidney (r= 0.68;p= 0.03;n= 10) recipients. To confirm our findings, we prospectively administered the ERMBT on multiple occasions to 20 patients who were undergoing kidney transplantation. Although the transplant physicians were blinded to the ERMBT results, the test predicted the stable daily doses of cyclosporine that they ultimately prescribed to the patients (r= 0.54;p= 0.015). When data from all 39 patients were pooled and subjected to multiple regression analysis, the ERMBT was the only variable examined that significantly correlated with the stable daily cyclosporine dose (r = 0.63;p<0.001;n= 39). In the 20 patients prospectively studied, the prescribed daily dose of cyclosporine generally decreased during the months after surgery and the percentage changes in cyclosporine daily dose correlated with changes in P450 3A activity during this period (r =0.47;p= 0.03). We conclude that interpatient and intrapatient differences in P450 3A activity in part account for the cyclosporine dosing practices of transplant physicians.Clinical Pharmacology and Therapeutics(1994)56,253–260; doi:10.1038/clpt.1994.1

ISSN:0009-9236    

DOI:10.1038/clpt.1994.135

年代:1994

数据来源: WILEY

摘要:

ObjectiveWe determined the possible benefits of a new opioid, trefentanil, relative to fentanyl and alfentanil using high‐resolution pharmacokinetic‐pharmacodynamic modeling and computer simulations of clinical dosing scenarios.MethodsFirst, we determined in nine volunteers the electroencephalographic (EEG) effects and the trefentanil infusion rate that gave maximal EEG changes in 3 to 10 minutes. Then, in a crossover fashion in five volunteers, we compared the pharmacokinetics and EEG pharmacodynamics of trefentanil with fentanyl and alfentanil. Finally, we used computer simulations to predict offset of opioid effects of trefentanil, fentanyl, and alfentanil when given in different dosing schemes.ResultsThe pharmacokinetic‐pharmacodynamic profile of trefentanil was similar to alfentanil, except for a higher elimination clearance. Trefentanil versus alfentanil pharmacokinetic parameters were as follows: Elimination clearance, 0.444 ± 0.073 versus 0.184 ± 0.031 L/min; steady‐state distribution volume, 37 ± 7 versus 23 ± 3 L; and elimination half‐life, 127 ± 24 versus 114 ± 19 minutes. Trefentanil versus alfentanil pharmacodynamics were as follows: the equilibration half‐time between EEG effect and arterial drug concentration, 1.2 ± 0.5 versus 0.6 ± 0.4 minutes; and the concentration resulting in 50% of maximal EEG effect, 429 ±313 versus 577 ± 273 ng/ml. The pharmacokinetic‐pharmacodynamic profile of fentanyl was significantly different from trefentanil and alfentanil. Simulation of effect compartment concentration decay curves after variable‐length infusions predicted more rapid recovery from trefentanil than from alfentanil or fentanyl.ConclusionWe suggest that high‐resolution pharmacokinetic‐pharmacodynamic studies and computer simulations of clinical dosing scenarios may have significant usefulness in appreciating differences between new and established drugs in early phase I studies.Clinical Pharmacology and Therapeutics(1994)56,261

ISSN:0009-9236    

DOI:10.1038/clpt.1994.136

年代:1994

数据来源: WILEY

摘要:

Zidovudine is metabolized to an inactive 5'‐glucuronide and has a short plasma half‐life requiring frequent dosing. The present study in six patients without symptoms who were infected with human immunodeficiency virus was undertaken to determine if coadministration of valproic acid which, like zidovudine, is metabolized by glucuronidation, would alter zidovudine disposition. Under steady‐state conditions for both drugs, the plasma area under the curve for zidovudine increased twofold with a corresponding decline in its oral clearance when given with valproic acid. The mean 5'‐glucuronide/zidovudine urinary excretion ratio was reduced by more than 50%, and the amount of unconjugated zidovudine recovered in urine increased by more than twofold. There was no significant increase in the plasma half‐life of zidovudine. The effects of valproic acid on zidovudine glucuronidation were related to plasma valproic acid concentrations. Valproic acid inhibits glucuronidation of zidovudine and increases its oral bioavailability.Clinical Pharmacology and Therapeutics(1994)56,272–278; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1994.137

年代:1994

数据来源: WILEY

摘要:

Differences in extent of amoxicillin absorption from various regions of the gastrointestinal tract were determined and compared with the same dose administered orally. Nine healthy men were intubated at a proximal (duodenum or jejunum) or distal (ileum or colon) site with use of a 15‐foot double lumen nasointestinal tube. Amoxicillin solutions (375 mg in 120 ml water) were delivered on 2 successive days as a bolus or a 4‐hour infusion. Subjects were reintubated at another site and amoxicillin administration was repeated. Subjects with colonie intubation received only infusions. Finally, all subjects received an oral dose of amoxicillin solution. Plasma samples were obtained at 16 time points over a 10‐hour period and assayed for amoxicillin by use of an HPLC method. Area under the concentration‐time curve and the maximum plasma concentration were computed to evaluate amoxicillin absorption. Amoxicillin absorption was rate and site dependent in the gastrointestinal tract. The drug was well absorbed in the duodenum and jejunum, with no significant differences in absorption when administered as a bolus or 4‐hour infusion, but absorption was decreased and rate dependent in the ileum, where more drug was absorbed as an infusion compared with a bolus. Amoxicillin was unabsorbed when infused in all colonie regions.Clinical Pharmacology and Therapeutics(1994)56,279–285; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1994.138

年代:1994

数据来源: WILEY

摘要:

ObjectiveTo apply a combined pharmacokinetic‐pharmacodynamic model to data from warfarin drug interaction studies.MethodsThe pharmacokinetic model for warfarin enantiomers combined a common first‐order absorption process with individual clearance and volume of distribution values and is based on unbound drug. The complete pharmacodynamic model comprised two components: that involving inhibition of pro‐thrombin complex activity (PCA) synthesis described by a sigmoid maximum effect (Emax) model and that relating temporal changes in PCA to synthesis and degradation. The combined model was applied to prothrombin time and plasma concentration‐time data obtained after oral administration of single doses of racemic warfarin to healthy subjects either alone or during multiple dosing with the metabolic enzyme inhibitor phenylbutazone or the inducer secobarbital.ResultsThe five parameters associated with the complete pharmacodynamic model were kd(0.054 ± 0.014 hr−1), the degradation rate constant of PCA; Cu50,S(0.0026 ± 0.0015 mg • L−1) and Cu50,R(3.45 ± 4.20 mg • L−1), the unbound concentrations of(S)‐ and(R)‐warfarin required to produce a 50% reduction in PCA synthesis if administered individually; γ (0.90 ± 0.23), the slope parameter in the sigmoid Emaxmodel; and td(8.2 ± 0.3 hours), the observed delay in the onset of warfarin anticoagulant response.ConclusionsThese findings qualitatively confirm the known potency difference between warfarin enantiomers. Furthermore, although phenylbutazone and secobarbital altered the pharmacokinetics of warfarin, these compounds do not appear to influence its pharmacodynamics. Simulation studies indicate that, after racemate administration, the continual presence of the more potent (S)‐enantiomer precludes accurate assessment of Cu50,R. Analysis indicates that use of racemic (rather than enantiomer) warfarin concentration data in drug interaction studies may lead to misinterpret

ISSN:0009-9236    

DOI:10.1038/clpt.1994.139

年代:1994

数据来源: WILEY

摘要:

ObjectiveTo establish whether the antihistamine cetirizine has the potential to prolong the QTCinterval in normal volunteers at up to six times the usual recommended dose.MethodsTwenty‐five healthy volunteers were studied in a prospective, double‐blind crossover design conducted on inpatients in a Clinical Research Center. The primary end point of the study was QTCprolongation on the surface electrocardiogram (ECG). Plasma concentrations of cetirizine were also measured for pharmacokinetic analysis. The end point for the pharmacokinetic analysis was the dose/area under the concentration‐time curve (apparent clearance of an oral dose). The subjects received the following three treatments in random sequence: placebo, 20 mg/day cetirizine, and 60 mg/day cetirizine for 7 consecutive days. A series of baseline ECGs was recorded over 2 days before each treatment, while the subject receiving placebo. ECG effects of the treatments were then compared with the baseline ECGs.ResultsAnalysis of variance showed no difference between the treatment groups (placebo, 20 mg cetirizine, and 60 mg cetirizine every day) in effect on QTCcompared with baseline. A paired Studentttest showed no difference in dose/area under the concentration‐time curve between the 20 mg/day and 60 mg/day dosing groups at steady state.ConclusionIn healthy volunteers, cetirizine does not prolong the QTCinterval at doses of up to six times the usual recommended dose.Clinical Pharmacology and Therapeutics(1994)56,295–301; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1994.140

年代:1994

数据来源: WILEY