摘要:

Magnetic resonance spectroscopy of fluorine (19F) has been used to noninvasively study the in vivo pharmacokinetics of a model drug, fleroxacin (a fluoroquinolone antibiotic agent), in healthy human subjects. After oral administration, fleroxacin was detected in19F magnetic resonance spectra from both liver and calf muscle and four magnetic resonance examinations were undertaken during a 24‐hour period. By combining plasma analysis by high performance liquid chromatography with the magnetic resonance data, the following pharmacokinetic parameters (mean values) were obtained: tmax, 1.4, 4.6, and 5.6 hours in liver, plasma, and muscle, respectively; Cmax, 53, about 250, and about 60 μmol/L in plasma, liver, and muscle, respectively; t1/2, 4.4 hours (fast phase) and 10.8 hours (slow phase) in liver and 14.2 hours in plasma. The study documents for the first time the potential use of19F magnetic resonance spectroscopy to noninvasively observe the time‐related changes of a fluorine‐containing drug in human tissues after oral administration.Clinical Pharmacology and Therapeutics(1990)48,481–489; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1990.183

年代:1990

数据来源: WILEY

摘要:

AminopyrineN‐demethylase activity and the contents of cytochrome P‐450, cytochrome b5, and NADPH‐reductase activity in human liver microsomes from 31 different patients were studied. Our results show the existence of significant interindividual, but not sex‐ or age‐related differencesN‐demethylase activity (ranging between 0.52 and 4.42 nmol/min/mg protein), and that these differences are directly correlated with the content of cytochrome P‐450 and NADPH‐reductase activity, but not with that of cytochrome b5content, in the samples. In contrast, no differences were found in the Michaelis‐Menten constant values for aminopyrine (mean, 2.4 mmol/L) or NADPH (mean, 69 μmol/L), strongly suggesting that interindividual differences could be due to the occurrence of different amounts of the same enzyme, rather than the presence of different enzymes, in the population studied.Clinical Pharmacology and Therapeutics(1990)48,490–495; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1990.184

年代:1990

数据来源: WILEY

摘要:

A single oral 5 mg dose of diazepam was given to 16 healthy native Chinese Han volunteers. Eight volunteers were extensive metabolizers of S‐mephenytoin” and eight were poor metabolizers of S‐mephenytoin. Plasma levels of diazepam and its demethyl metabolite were determined by HPLC in blood samples drawn during 4 weeks. There was no difference in diazepam disposition between the two phenotypes. However, the plasma half‐life of demethyldiazepam was longer in poor metabolizers than in extensive metabolizers of mephenytoin (mean ± SD: 161 ± 37 and 116 ± 29 hours, respectively;p<0.02). The plasma concentrations of demethyldiazepam at 7, 14, and 21 days after intake of diazepam were significantly higher in poor metabolizers than in extensive metabolizers. We compared the pharmacokinetic parameters of diazepam in Chinese subjects with our previously reported data from white subjects. The mean plasma half‐life values of diazepam in Chinese extensive metabolizers (85.1 hours) and poor metabolizers (88.3 hours) were very similar to those in white subjects who were poor metabolizers (88.3 hours), and more than twice those in white subjects who were extensive metabolizers (40.8 hours). In parallel, the mean clearance of diazepam in Chinese subjects (independent of phenotype) was similar to that in white subjects who were poor metabolizers, but half that in white subjects who were extensive metabolizers. Chinese subjects had a slightly larger volume of distribution of diazepam than white subjects. This study showed that the metabolism of diazepam was slow in both extensive metabolizers and poor metabolizers of mephenytoin among Chinese subjects and similar to that in white subjects who were poor metabolizers. This indicates that there are interethnic differences not only in the incidence of poor metabolizers of mephenytoin but also in the substrate specificity of the S‐mephenytoin hydroxylase.Clinical Pharmacology and Therapeutics(1990)48,496–502; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1990.185

年代:1990

数据来源: WILEY

摘要:

In clinical practice, estimations of renal function are commonly used to calculate the appropriate dose for drugs that are renally cleared. Continuous‐infusion inulin clearance (CLIN), 4‐hour creatinine clearance (CLCR,m), and 24‐hour creatinine clearance (CLCR,a) were measured in 109 subjects (86 men and 23 women) with varying degrees of stable renal function (CLIN, 6 to 209 ml/min) and compared with CLCRvalues as predicted by five equations on the basis of plasma creatinine concentrations, age, weight, and/ or height. The CLCR,mwas positively correlated with CLIN(r= 0.92;p<0.0001) but exceeded CLINby 15% between the range of 30 and 209 ml/min (CLIN). Similarly, CLCR,acorrelated well with both CLCR,m(r= 0.84;p<0.0005) and CLIN(r= 0.84;p<0.0001). The relative role of tubular secretion in the overall clearance of creatinine increased with declining CLINand exceeded 40% when CLINwas below 30 ml/min. CLCRestimated by the Cockcroft‐Gault and Mawer methods did not significantly differ from either CLCR,mor CLCR,a, whereas the other equations generally underestimated CLCR. Among the numerous mathematical equations, CLCRas estimated by the method proposed either by Mawer or Cockcroft and Gault was the best predictor of CLIN(CLIN= 1.05CLCR−18.38 or CLIN= 1.12CLCR−20.60, respectively;r= 0.81;p<0.0001). The present data support the use of estimator equations proposed by Cockcroft and Gault or Mawer for rapid estimation of renal function in the clinical setting.Clinical Pharmacology and Therapeutics(1990)48,503–508; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1990.186

年代:1990

数据来源: WILEY

摘要:

Labetalol pharmacokinetics and pharmacodynamics were evaluated in nine subjects before and during enzyme inhibition with Cimetidine. Pharmacologic response was assessed by use of standardized treadmill tests during 24 hours after administration of oral labetalol. Oral clearance of labetalol decreased with Cimetidine administration (58.7 ± 23.3 to 32.9 ± 13.2 ml/min/kg;p<0.05), thereby causing a 79% increase in area under the curve. Labetalol systemic clearance also decreased (23.2 ± 5.3 to 17.7 ± 3.7 ml/min/kg;p<0.05), but the volume of distribution was unchanged. Labetalol caused significant ß‐blockade for 8 hours after the last oral dose, but Cimetidine did not alter pharmacologic response. The Emaxmodel provided a good description of the concentration‐effect relationship. At peak labetalol concentrations after oral administration, (R,R)‐labetalol concentrations were significantly lower than those of the other three stereoisomers (p<0.05). Cimetidine caused an increase in the concentrations of each stereoisomer, but the difference was significant (p<0.05) for only the (S,R)‐, (S,S)‐, and (R,S)‐isomers. This first evidence of labetalol stereoselective disposition is consistent with the findings of previous (R,R)‐labetalol pharmacokinetic studies and with previous pharmacodynamic investigations of labetalol and (R,R)‐labetalol.Clinical Pharmacology and Therapeutics(1990)48,509–519; do

ISSN:0009-9236    

DOI:10.1038/clpt.1990.187

年代:1990

数据来源: WILEY

摘要:

In this study we evaluated subjects with Down's syndrome for the possibility that direct or indirect gene dosage effects of trisomy 21 alter the fate of acetaminophen. We also investigated the usefulness of noninvasive sampling techniques to obtain parameter estimates for drug disposition in these developmentally disabled individuals. After administration of 5 mg/kg and 20 mg/kg oral doses of acetaminophen, subjects with Down's syndrome resembled control subjects in most pharmacokinetic and metabolic parameters, including apparent half‐life, volume of distribution per kilogram body mass, total body clearance per kilogram of body mass, extrapolated saliva concentration at time zero, and the urinary excretion of acetaminophen glucuronide and sulfate conjugates. Glutathione conjugation tended to increase and sulfate conjugation tended to decrease in all subjects as the acetaminophen dose increased from 5 mg/kg to 20 mg/kg. Results based on these samples of very limited size also suggest that acetaminophen metabolism to glutathione‐derived conjugates may have been increased in subjects with Down's syndrome. The similarity of estimates of acetaminophen pharmacokinetics and data on metabolic fate between subjects with Down's syndrome and normal volunteers indicates that large effects of trisomy 21 on these processes are unlikely. Also, these results were in agreement with extensive data obtained with invasive techniques, indicating that simple noninvasive methodologies appear to be well suited for studying acetaminophen disposition in populations of developmentally disabled individuals.Clinical Pharmacology and Therapeutics(1990)48,520–528; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1990.188

年代:1990

数据来源: WILEY

摘要:

Thirteen healthy female volunteers with regular menstrual cycles (28 ± 2 days) received 25 gm oral and 5 gm intravenous doses of D‐xylose on 2 successive days during the follicular, ovulatory, and luteal phases of two consecutive menstrual cycles. The ovulation time was characterized by luteinizing hormone levels, body basal temperatures, and progesterone and estradiol serum levels. D‐Xylose was assayed in plasma and urine with a phloroglucinol‐based colorimetric method. The findings of this study indicated that menstrual cycle did not significantly affect D‐xylose absorption. After oral administration, the total clearance was significantly increased in cycle 2 during the luteal phase (p= 0.004). After intravenous administration in both cycles, D‐xylose total clearance was also singificantly faster during the luteal phase (p= 0.038 andp= 0.041, respectively). After oral administration, the renal clearance tended to be higher during the luteal phase in both cycles studied. After intravenous administration, this parameter was increased during the luteal phase by 24% and 25% in cycle 1 and by 8% and 12% in cycle 2. These findings are consistent with those of others showing an increase in glomerular filtration rate (GFR) during the luteal phase of the menstrual cycle. The findings of this study seem to be explained by the hormonal changes occurring during the menstrual cycle. Further investigations are warranted with use of specific probes of renal processes (GFR, renal reabsorption and tubular secretion) to confirm our findings and to elucidate the underlying mechanisms.Clinical Pharmacology and Therapeutics(1990)48,529–536; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1990.189

年代:1990

数据来源: WILEY

摘要:

The α1‐ and α2‐adrenergic venoconstriction in dorsal hand veins of normal subjects was determined by infusion of phenylephrine or clonidine. Oral administration of prazosin reduced the constriction response to phenylephrine but not to clonidine. Subjects were treated for 3 weeks in a randomized crossover design with placebo or guanadrel sulfate. Guanadrel reduced sympathetic tone (i.e., plasma norepinephrine and norepinephrine release rate), whereas venous responses to phenylephrine and clonidine were both augmented during guanadrel treatment. The effect on phenylephrine responses was primarily attributable to a decrease in the median effective concentration with a small increase in maximum response. Clonidine showed a markedly increased maximum response with a small increase in the median effective concentration. Platelet α2‐adrenergic receptors increased slightly but there was no change in the amount of platelet pertussis toxin substrate during guanadrel treatment. Thus reduction in sympathetic tone in normal young men results in increased venous responses to both α1‐ and α2‐agonists.Clinical Pharmacology and Therapeutics(1990)48,537–543; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1990.190

年代:1990

数据来源: WILEY

摘要:

The goal of this investigation was to determine a numerical electroencephalographic parameter that best indicated the degree of the effect of midazolam, administered in hypnotic doses, on the central nervous system. This electroencephalographic parameter could then be used to relate midazolam plasma concentrations and electroencephalographic drug effect (pharmacodynamic modeling). Intravenous doses of midazolam (3.75 to 25 mg) were given to five men at an infusion rate of 5 mg/min. A cortical electroencephalogram was continuously recorded. Two waveform analysis approaches were examined: fast Fourier transformation and aperiodic analysis. From fast Fourier transformation and aperiodic analysis a set of parameters were examined as measures of drug effect. We conclude that the voltage per second from aperiodic analysis provided the electroencephalographic parameter that optimally measured the effect of midazolam on the central nervous system.Clinical Pharmacology and Therapeutics(1990)48,544–554; doi:10.1038/clpt.1990.1

ISSN:0009-9236    

DOI:10.1038/clpt.1990.191

年代:1990

数据来源: WILEY

摘要:

The comparative pharmacodynamics of midazolam and diazepam were examined by use of the electroencephalogram as a measure of drug effect on the central nervous system. Intravenous doses of 7.5, 15, and 25 mg midazolam and 15, 30, and 50 mg diazepam were given on repeated occasions to three volunteers. Arterial plasma concentration and electroencephalogram voltage were related with nonparameteric and parametric pharmacodynamic models. The peak increases in voltage (maximal effect) and the slopes of the plasma concentration versus effect curve were similar for both drugs. The half‐time of blood:brain equilibration was significantly longer for midazolam than diazepam (4.8 minutes versus 1.6 minutes). Midazolam was found to have an intrinsic steady‐state potency that was approximately five times greater than that of diazepam (152 ng/ml versus 958 ng/ml).Clinical Pharmacology and Therapeutics(1990)48,555–567; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1990.192

年代:1990

数据来源: WILEY