摘要:

The importance of a more therapeutically oriented perspective for pharmacokinetics has been repeatedly advocated and stressed during the past few years. Review of recent publications in this field reveals that the search for solutions to clinically relevant problems is merely a secondary goal in many studies. Hence, to obtain reliable information which can be applied safely in therapeutic practice, studies need to be interpreted critically. After careful analysis of publications on some of the most representative drugs and drug groups (anti-infective agents, antiepileptic drugs, psychotherapeutic drugs, antiarrhythmic agents, digoxin, propranolol, theophylline, warfarin, anticancer agents), tentative guidelines are given for data for which the clinical relevance is well established, for findings for which the relevance should be checked in routine practice, for areas where much research is still needed before kinetic knowledge can result in improved therapeutic outcome, and for fields where only minor therapeutic advances can be expected from extended kinetic investigations.Within the general framework of clinical pharmacology, it appears that the use of pharmacokinetics is a fundamental research tool and a useful aid to therapeutic practice only if its limitations are clearly recognised, and if priority is given to creating favourable, controlled conditions for good diagnostic practice, general patient care and compliance of the patient with treatment.A restricted attitude is suggested toward the natural expansion of blood level monitoring, because of the risk that doctors and institutions become ‘dependent’ on this technique and lose their critical capacity in the use of both clinical and kinetic data.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The following summarises the contents of both this review and its predecessor in this journal (Iisalo, 1977). The two reviews should be read in conjunction with each other.Digoxin is absorbed mostly from the proximal part of the small intestine. About 67% is absorbed from tablets, 80% from elixir and up to 100% from encapsulated elixir. Protein binding of digoxin and its metabolites is low and of little clinical significance. Digoxin is widely distributed throughout body tissues and has a high apparent volume of distribution (about 6L/kg). Although most of the digoxin in the body is in skeletal muscle it is found in highest concentrations in the heart, kidneys and brain. The apparent volume of distribution is reduced in patients with renal impairment and in the elderly. Plasma digoxin concentrations do not closely reflect myocardial whole tissue concentrations.The half-time of elimination in healthy subjects averages 40 hours. In most patients, more than 80% of digoxin is excreted unchanged in the urine but in about 12% of patients between 20% and 55% is excreted as metabolites, mostly dihydrodigoxin, which is relatively inactive. In a few subjects other, more active, metabolites may be found in the urine. Renal elimination is mainly by glomerular filtration but some passive tubular reabsorption and active secretion occur.The relationships between plasma digoxin concentrations and its pharmacodynamic or therapeutic effects are not clear. However, plasma digoxin concentrations may relate well to theslowingof ventricular rate from pre-treatment values in atrial fibrillation but not torestingventricular rates. In cardiac failure in sinus rhythm, plasma digoxin concentrations may relate well to the inotropic effect of the drug but theoretical tissue digoxin concentrations may be more closely related.Digoxin passes across the placenta and into breast milk but not in sufficient quantities to prove harmful to the fetus or neonate.In renal impairment, the half-time of digoxin is prolonged and its apparent volume of distribution reduced.The pharmacokinetics of digoxin in different states of thyroid function are complex and do not fully explain, for example, the apparent ‘resistance’ to digoxin in hyperthyroidism.The most important digoxin-drug interactions are those involving quinidine and drugs which deplete the body of potassium.Plasma (or serum) digoxin concentration measurement may be of value in the diagnosis of toxicity or undertreatment, in overdose and in changing treatment in patients with renal impairment or on long term therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The elimination of quinidine in humans is accomplished by a combination of renal excretion of the intact drug (15 to 40% of total clearance) and hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance). Many of the metabolites appear to be pharmacologically active. Typical ranges for kinetic properties of quinidine in healthy persons are: apparent volume of distribution 2.0 to 3.5 litres/kg; elimination half-life 5 to 12 hours; clearance, 2.5 to 5.0ml/min/kg. Quinidine clearance is reduced in the elderly, in patients with cirrhosis, and in those with congestive heart failure.Oral quinidine is available either as relatively rapidly absorbed conventional tablets (usually quinidine sulphate) or as a variety of slowly absorbed sustained release preparations. Absolute systemic availability generally is 70% or greater.Quinidine is 70 to 95% bound to plasma protein, primarily to albumin but also to a number of other plasma constituents. Binding is reduced in patients with cirrhosis, partly because of hypoalbuminaemia, but is not influenced by renal insufficiency. Clinical interpretation of total serum or plasma quinidine concentrations must be altered in patients with reduced or increased binding, since it is the unbound fraction which is pharmacologically active.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The pharmacokinetics of metoprolol have been studied in a group of patients with varying degrees of renal impairment and in healthy subjects after administration of 20mg of metoprolol tartrate intravenously and 50mg orally in a single dose and during steady-state conditions.There were no significant differences in the extent of bioavailability or rate of elimination of the drug between the 2 groups. The fraction of the oral dose systemically available during steady-state was 59 ± 9% in the renal patients and 55 ± 7% in the control group. Total body clearance in the patients with renal failure was 1.0 ± 0.1L/min and in the healthy subjects it was 0.8 ± 0.1L/min. The corresponding values for the elimination half-life were 4.6 ± 1.2h and 4.1 ± 1.0h, respectively.The &bgr;-adrenoceptor blocking effect of metoprolol (determined as percent reduction of exercise heart rate) did not differ significantly between the 2 groups during steady-state conditions. The effect on exercise heart rate was linearly related to the log of the plasma concentration of metoprolol. The relationship was identical for the single dose and during steady-state conditions, indicuting that accumulation of metabolites in patients with renal failure does not influence the &bgr;-blocking properties of metoprolol.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Plasma concentration and urinary excretion of total and 2 active metabolites of metoprolol have been studied in patients with varying degrees of renal impairment and in healthy subjects after intravenous and oral administration of 20 and 50mg of3H-metoprolol tartrate respectively.Renal clearance of total metabolites correlated directly with51Cr-EDTA clearance (r = 0.95, p < 0.001). A reduction of glomerular filtration rate (GFR) by 70 to 80% increased the elimination half-life of total metabolites and of the active metabolite a-hydroxymetoprolol about 3-fold.Significant accumulation was, however, only observed in the patients with a GFR of about 5ml/min. Even in these patients, the contribution of a-hydroxymetoprolol to the &bgr;-adrenoceptor blocking effect of metoprolol will be negligible. The second active metabolite studied is eliminated via biotransformation, and the urinary excretion as well as the plasma concentration of this metabolite were extremely low in comparison with those of the parent drug.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The kinetics of tritiated metoprolol and its metabolites have been determined after intravenous and oral administration in dialysis patients. The kinetic behaviour of metoprolol in these patients does not differ from that in healthy volunteers, since its elimination depends on hepatic metabolism. The pharmacologically less active metabolite a-hydroxymetoprolol is formed to an individually varying degree and its half-life is prolonged. The concentration of the total radioactivity, which represents the sum of all metabolites, does not decline in the dialysis interval. During haemodialysis, however, its concentration decreases with a half-life of 5h. It might be assumed, that dialysis of these polar compounds is rather nonspecific and that it depends essentially on the dialysis technique.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS