ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The orally active angiotensin-converting inhibitors (ACE inhibitors) such as captopril and enalapril represent a significant therapeutic advance in the treatment of hypertension and congestive heart failure. Enalapril differs from captopril in several respects. It is a prodrug converted by hepatic esterolysis to the active (but more poorly absorbed) diacid, enalaprilat. Enalaprilat is more potent than captopril, more slowly eliminated and does not possess a sulfhydryl (SH) group.Enalapril was rapidly followed by a number of newer ACE inhibitors, the majority of which are similar to enalapril in that they are prodrugs, converted by hepatic esterolysis to a major active but poorly absorbed diacid metabolite. In one case (delapril) there are 2 active metabolites; in another (alacepril) the prodrug is convertedin vivoto captopril. Lisinopril is an exception in that it is an enalaprilat-like diacid but with acceptable oral bioavailability, so that the prodrug route is not employed. The newer ACE inhibitors are at widely different stages of development, and it is not yet clear how many will reach regular clinical use. Of these newer drugs, lisinopril is the longest established and is the subject of the widest published literature. For a number there is as yet little published pharmacokinetic information.A variety of assay methods have been employed to characterise the pharmacokinetics of the ACE inhibitors, including enzymatic techniques, radioimmunoassay and chromatography. The peak plasma concentrations of the prodrugs are generally observed at around 1 hour and those of the diacid metabolites at about 2 to 4 hours. However, there is considerable variation within and between drugs, with benazepril and benazeprilat reaching peak concentrations early and enalapril and enalaprilat typical of later times to peak. Absorption of the active diacids is generally poor, and moderate (typically 30 to 70%) for the prodrugs. The bioavailability of lisinopril is about 25%.It is difficult to talk meaningfully about half-lives of the active drugs. The declines in their plasma concentrations are polyphasic and, if analytical sensitivity allows, active drug may be found at 48 hours or more following administration. This may reflect binding to ACE in plasma. Half-lives of accumulation are of the order of 12 hours; protein binding varies from little (lisinopril) to 90% (benazeprilat). Elimination is mostly renal but there may be biliary elimination for some, such as benazeprilat and fosinopril. The half-lives of the prodrugs are short.Impaired renal function decreases the elimination rate of the diacids. The largest effects on plasma concentrations are associated with severe renal impairment (glomerular filtration rate; < 30 ml/min). Increasing renal impairment is associated with longer times to peak of the diacids. Lisinopril and enalaprilat have been shown to be dialysable. Increasing age has variable effects, but is often accompanied by a decreased rate of elimination related to renal function, best demonstrated in population pharmacokinetic studies. Congestive heart failure may be associated with higher plasma concentrations but the pharmacokinetics of these agents in uncomplicated essential hypertension appear to be normal. The effects of hepatic impairment have been little studied, but severe hepatic impairment would be expected to result in impaired esterolysis of the prodrugs.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Ketoprofen, a potent nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, has been used clinically for over 15 years in Europe, and has recently been introduced in the United States. Although it possesses a chiral centre, with only theS-enantiomer possessing beneficial pharmacological activity, all ketoprofen preparations to date are marketed as the racemate. Ketoprofen exhibits little stereoselectivity in its pharmacokinetics. The enantiomers have similar plasma time-courses and do not seem to interact with one another. Hence, the data generated using nonstereospecific assays may be used to explain the pharmacokinetics of individual enantiomers.The absorption of ketoprofen is rapid and almost complete when given orally. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase half-life of ketoprofen (1 to 3h). They may also decrease local gastrointestinal side effects. Although with these preparations the peak plasma drug concentration is reduced and time to peak is prolonged, the bioavailability is the same as that with regular release counterparts. Ketoprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, the proposed site of action of NSAIDs. It is eliminated following extensive biotransformation to inactive glucuroconjugated metabolite. There is about 10%RtoSinversion upon oral administration. Conjugates are excreted in urine, and virtually no drug is eliminated unchanged. The excretion of conjugates is closely tied to renal function; accumulation of conjugates occurs in the elderly, but not in young subjects or patients. Significant drug interactions have been demonstrated for probenecid, aspirin and methotrexate. There appears to be circadian variation, particularly in the absorption of ketoprofen. The relationship between concentration and anti-inflammatory effect has yet to be elucidated for this drug.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Part I of this article, which appeared in the previous issue of the Journal, discussed the implications of variations in plasma protein levels in a number of diseases: hepatic and renal disease, acute myocardial infarction, burns, cancer, diabetes mellitus, hyperlipidaemia and inflammatory diseases. In Part II the authors continue their review with a further range of disease states, and consider their import for drug dosages.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The pharmacokinetics of atracurium, laudanosine and the quaternary alcohol were studied in patients with normal and impaired renal function following intravenous administration of atracurium. Anaesthesia consisted of thiopental, fentanyl, halothane and nitrous oxide in oxygen. Plasma and urine concentrations of the parent compound and its degradation products were measured by high performance liquid chromatography. Renal failure was defined as a creatinine clearance of less than 5 ml/min; it caused no significant differences in the pharmacokinetics of atracurium but did result in a different pharmacokinetic profile of laudanosine, with a 3-fold increase in the mean (± SD) terminal half-life (176 ± 84 and 516 ± 262 minutes for patients with normal and impaired renal function, respectively). Moreover, the half-life of the quaternary alcohol increased from 27.1 ± 8.3 minutes in patients with normal renal function to 42.5 ± 8.3 minutes in those with impaired renal function (mean ± SD). Renal elimination of unchanged atracurium accounted for 11% of the administered dose and at least 27% of the total degradation of atracurium occurred via ester hydrolysis.The neuromuscular function was monitored by measuring the twitch tension of the adductor pollicis muscle elicited by stimulation of the ulnar nerve at 0.1Hz. The total duration of neuromuscular blockade (51.8 ± 11.5 minutes) and the recovery index (9.6 ± 2.0 minutes) are shortened in patients with impaired renal function, compared with those with normal renal function (64.1 ± 7.2 and 16.7 ± 4.1 minutes, respectively), indicating that sensitivity to the neuromuscular blocking action of atracurium may be altered by renal failure.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

A steady-state model is here developed as a framework for the analysis of blood concentrations of clomipramine, obtained during routine drug monitoring. A model is proposed to account for its major metabolic pathways, hydroxylation and demethylation, including first-pass effect. Impaired hydroxylation capacity is shown to lead to a dramatic increase in the concentration of demethyl-clomipramine, with a concomitant moderate increase in that of the parent drug. Deficient demethylation capacity is associated with a reduced ratio of demethyl metabolite to parent drug. A nomogram is provided to allow easy determination of hydroxylation and demethylation capacities from routinely measured blood concentrations.Data from 150 patients are analysed in order to identify interindividual variability factors. Average pseudo-clearances, calculated from trough blood concentrations at steadystate, are 17 L/h for hydroxylation, 23 L/h for demethylation and 40 L/h for elimination of hydroxylated metabolites. Maximum to minimum ratios are 8, 27 and 11, respectively. The metabolising capacity through either process significantly decreases with increasing age, clearance estimates being 40 to 50% lower for patients 75 years or older than for those 40 years or younger. Tobacco smoking and chronic alcohol consumption induce and reduce the demethylation clearance, respectively. Inhibition of hydroxylation in the presence of phenothiazine comedication is also shown. Finally, small but significant differences according to sex are observed.Potential implications of the proposed model-based approach include adaptation of the dosage regimen to individual characteristics at the very beginning of antidepressant therapy, and early detection of patients with impaired metabolising capacities.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS