ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The advantages and limitations of the 2 most commonly used methods to investigate interindividual pharmacokinetic variations are reviewed. The first method is based on pharmacokinetic comparisons made after repeated administration of a model drug such as antipyrine, before, during and after imposition of a carefully controlled environmental perturbation. A principal virtue of the test is the use of each subject as a control. Subjects are usually under near basal conditions with respect to factors capable of altering hepatic drug-metabolising capacity. Exceedingly sensitive, the test yields highly reproducible results. It has been useful as a research tool in identifying environmental factors for which dose-response curves can be generated and compared. However, the test requires careful selection and control of subjects, and it may be hazardous to extrapolate results to subjects under different, non-basal, environmental conditions. This method most frequently involves antipyrine as the test compound, but other drugs can and have been used. The results disclose that many host factors that influence antipyrine disposition also affect the disposition of other drugs metabolised by hepatic mixed-function oxidases.Recent refinement of the antipyrine test involves measurement of the rate constant for formation of each of the 3 main metabolites of antipyrine. Sensitivity and specificity of the test are increased through examination of the effect of each factor on a separate hepatic cytochrome P-450. Due to the labouriousness of this procedure and its requirement for several days of urine collection from each subject, metabolite analysis will probably remain an experimental method not applicable for screening populations.The second method involves a particular model based on multiple regression analysis. Relying on correlations with historical data of a qualitative nature, previous applications of this method have been retrospective, rather than prospective. Several such correlations could not be confirmed in normal subjects under the conditions of a controlled prospective experiment. Thus, prospective studies need to be performed to check results obtained with this method. The model used appears to enjoy certain advantages, including speed, simplicity, and ease of execution. Since in all its previous applications only a single rate measurement has been performed in each subject, the method is more conveniently employed than the antipyrine test to screen large numbers of environmentally perturbed subjects, i.e. the method seems attractive under ‘real world’ conditions. Nevertheless, this method as used has disadvantages. In past applications no controls have been included and only parent drug, rather than metabolites, has been measured. Also, reproducibility of results in a given population has not been firmly established and since very few subjects are usually studied, compared with the large number of variables and environmental perturbations represented, it is dubious whether the subjects reliably reflect the much larger population from which they are drawn. This is because of the difficulty of defining quantitatively in each perturbed subject precisely how much each host factor contributes to the observed rate of drug elimination. The more environmentally perturbed the subjects selected for study, the more interindividual variation will probably occur in their response to drugs; the model used ignores these problems, and accordingly in such environmentally perturbed subjects, genetic factors have been concealed and inaccurately estimated. Any given environmental factor is considered by the model to produce similar pharmacokinetic effects in all subjects, whereas extensive interindividual variability in such responses occurs for which the model as used does not compensate.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Plasma concentrations of glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide 2- and 5-mononitrates in man have been measured after administration via different routes. Appropriate precautions have to be taken in the administration of these agents (to avoid loss during intravenous infusion), and in their sampling and assay. Pharmacokinetic calculations based on plasma concentrations should be viewed with caution, as the data on which these calculations are based are often very limited, and the very rapid disappearance of for example glyceryl trinitrate from plasma makes the choice of an appropriate kinetic model and exact calculations difficult.Glyceryl trinitrate disappears from plasma within a few minutes, and a high apparent volume of distribution and a very high systemic clearance are found. After oral administration, plasma concentrations are very low; with sublingual or cutaneous administration, higher plasma concentrations can be obtained, suggesting a high first-pass extraction after oral administration, but quantitative data on bioavailability are lacking.For isosorbide dinitrate the systemic clearance, although high, is lower than for glyceryl trinitrate; disappearance from the plasma is slower and plasma concentrations after different routes of administration are much higher. Here too, quantitative data on bioavailability are lacking.High plasma concentrations of isosorbide 2-mononitrate and isosorbide 5-mononitrate are found in plasma after administration of isosorbide dinitrate. These metabolites have a good bioavailability, and half-lives of around 2.5 hours for isosorbide 2-mononitrate and 5 hours for isosorbide 5-mononitrate.Only very limited data are available about the influence of disease states and interactions with food and other drugs on the kinetics of the organic nitrates.It is very difficult to correlate the effects of the nitrates to their plasma concentrations; counter-regulation, development of tolerance, and the presence of metabolites could disturb the interpretation of such a relationship. It is at present impossible to predict the pharmacological effects or the efficacy of organic nitrates on the basis of their plasma concentrations.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Fentanyl, a synthetic opiate with a (clinical) potency of 50 to 100 times that of morphine, was introduced into clinical practice in the early 1960s. Usually administered by single intravenous doses, it developed a reputation for having a short duration of action and it was assumed that this was a consequence of rapid removal from the body. However, as clinical experience increased, it was realised that administration of multiple doses or large doses during narcotic-based anaesthesia sometimes led to delayed recovery and prolonged respiratory depression, suggesting that the duration of action was limited by redistribution within the body rather than removal from the body. Recent developments in analytical techniques have allowed pharmacokinetic studies and these have confirmed this opinion; fentanyl is rightly regarded as having a redistribution-limited duration of action after single or infrequent doses (analogous to thiopentone). However, the magnitude of the pharmacokinetic constants reported for fentanyl are remarkably inconsistent even in healthy volunteers, for reasons apparently only explainable by assay differences. Hence, estimates of apparent volume of distribution (area) range from around 60L to over 300L, estimates of terminal half-life range from about 1.5 to 6 hours (15 hours in geriatric patients) and total body clearance ranges from 0.4 to over 1.5 L/min. Renal excretion accounts for up to 10% of the dose; the remainder of the clearance would appear to be predominantly hepatic, but with contributions from other tissues.Continued clinical developments of narcotic-based anaesthetic techniques have resulted in high doses of narcotic being used, with oxygen, as the sole anaesthetic agents. At present these techniques are usually based on fentanyl, and the technique is frequently called ‘stress-free anaesthesia’ because of the effects in obtunding the ‘stress response’ caused by surgery (elevation of plasma concentrations of cortisol, glucose, ADH, etc. in the intra- and postoperative period) and the lack of deleterious effects on the cardiovascular system.With the hypothesis that increased potency is associated with increased specific opiate effects and decreased nonspecific cardiovascular depressant effects, chemical congeners of fentanyl were developed. Alfentanil has about one-third the (clinical) potency of fentanyl, while sufentanil has about 5 to 10 times the (clinical) potency of fentanyl. Lofentanil and carfentanil have about 20 to 30 times the potency of fentanyl and have yet to find clinical roles.Alfentanil is characterised by a rather small apparent volume of distribution for a base (Varea= 40-70L), short terminal half-life (100 minutes), intermediate total body clearance (0.3-0.5 L/min) and negligible renal clearance. Sufentanil would appear to have pharmacokinetic properties intermediate to those of alfentanil and fentanyl.At physiological pH, approximately 15 to 20% of fentanyl is unbound in plasma compared with 5 to 10% of alfentanil, sufentanil and lofentanil. Except for alfentanil, there is a marked plasma binding dependence on pH. Also except for alfentanil, there is a predominance of ionised drug species and a high octanol: water partition coefficient in the physiological pH range. These factors act to influence the tissue binding of the agents and reflect back on other important factors such as uptake by blood cells. Whole blood: plasma concentration ratios of 0.97, 0.63, 0.74 and 0.71 have been reported for fentanyl, alfentanil, sufentanil and lofentanil, respectively.The range of opiate duration of action has been extended by the appearance of these newer compounds, where alfentanil may be regarded as having an ultrashort duration of action, fentanyl and sufentanil as short acting, while lofentanil has a long duration of action. Knowledge of the pharmacokinetic properties of these agents has provided more information than could be obtained from clinical studies alone, and has added a basis on which to rationalise and enhance their usefulness.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The serum concentration-time curve of valproic acid was followed in 25 children after single oral doses of the drug and at steady-state. Total body clearance (CL), half-life (t½), and apparent volume of distribution (Vd) were calculated from the terminal portion of the curve and from the area under the serum concentration-time curve (AUC). The CL and Vd were significantly greater at steady-state (0.42 ± 0.20 ml/min/kg and 0.231 ± 0.067 L/kg, respectively) than after a single dose (0.32 ± 0.13 ml/min/kg and 0.191 ± 0.055 L/kg, respectively). This difference was most pronounced in patients with valproic acid dosage increases in excess of 20% and no change in their concurrent anticonvulsant therapy between the single-dose and steady-state study periods. The t½was not significantly different between the 2 study periods.There was a significant correlation between age and both CL and Vd after single doses and at steady-state. The t½did not appear to be age related.These results suggest that the adequacy of the dosage regimen must be determined during maintenance therapy rather than extrapolated from data obtained after a single dose. Re-evaluation of therapy as the child grows older may also be necessary in view of the age-related differences in valproic acid pharmacokinetics which this study has demonstrated.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The ability of a new multiple-dose non-linear regression analysis program to predict steady-state aminoglycoside peak and trough serum concentrations was evaluated. 30 patients receiving either amikacin (7), gentamicin (10) or tobramycin (13) were studied. A standard method of prediction which requires the collection of 3 or 4 serum samples during a dosing interval and a predictive method which relies upon population-based estimates of pharmacokinetic parameters were compared with the new approach which requires the collection of 2 serum samples. There were no significant differences between the methods which utilised serum concentration data with regard to predictive precision (mean prediction error of about 10%). These methods were more precise than the population-based method (p < 0.01, mean prediction error 29.1%). None of the methods produced biased estimates.These results indicate that when the regression program is employed, valid estimates of pharmacokinetic parameters and prediction of steady-state serum concentrations can be obtained with fewer serum samples than have been recommended.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS