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1. |
Clinical Pharmacokinetics and Endocrine Disorders Therapeutic Implications |
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Clinical Pharmacokinetics,
Volume 13,
Issue 6,
1987,
Page 345-364
Patricia O'Connor,
John Feely,
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摘要:
Endocrine disorders are common and produce widespread changes in cellular and organ function. Alterations in the sensitivity of patients with thyroid disorders to digoxin. anticoagulants and sedatives have been recognised for many years. Many of the recently documented kinetic alterations in endocrine patients are explicable on the basis of diseaseinduced changes in hepatic drug metabolism, protein binding and renal function.In hyperthyroidism the rate of absorption of paracetamol, propranolol and oxazepam is increased due to increased gastrointestinal motility. The volume of distribution of propranolol and digoxin is increased and there is decreased binding of both basic and acidic drugs as a consequence of alterations in &agr;1-acid glycoprotein and albumin concentration. The rate of glucuronidation of paracetamol and oxazepam is increased in hyperthyroidism. While oxidative metabolism of antipyrine, propranolol, metoprolol and theophylline is enhanced, the clearance of a number of other agents, including diazepam, warfarin. antithyroid drugs and phenytoin, is unaltered. The systemic clearance of propranolol is enhanced as a consequence of a 50% increase in liver blood flow. The rate of elimination of a number of endogenous substances, including cortisol, thyroid hormones and insulin, also appear to be enhanced. Hyperthyroidism has a variable effect on renal function, with a possible increase in digoxin elimination, but no effect on the clearance of renally excreted &bgr;-blockers, atenolol, sotalol and nadolol. These kinetic changes suggest that individualisation and higher than normal dosage of propranolol is necessary to control hyperthyroidism, and in thyrotoxic atrial fibrillation higher doses of digoxin or additional therapy with &bgr;-blockers, or verapamil, may be indicated. The increased sensitivity of thyrotoxic patients to warfarin suggests care with dosage and frequent monitoring of response are warranted.Less information is available concerning hypothyroidism, but there is a general trend for decreased absorption of paracetamol and propranolol. In addition, the volume of distribution of digoxin is reduced, as is renal clearance. Limited studies suggest no alteration in the glucuronidation of oxazepam, but antipyrine clearance appears to be reduced. Steadystate propranolol concentrations are elevated in hypothyroidism and there appears to be a decreased metabolism of thyroid hormones and cortisol. Preliminary information suggests the binding of propranolol is increased. Thus, in the treatment of hypothyroid patients, a lower dosage of propranolol may be required. These patients also appear to be extremely sensitive to digoxin, partly because of decreased renal elimination and distribution; thus a smaller maintenance and loading dose is required. Increased sensitivity to oxazepam has been recorded, which cannot be explained on the basis of kinetic alterations.Obesity may produce profound alterations in kinetics, particularly distribution. A small increase in the volume of distribution of cimetidine, prednisolone and digoxin, and a moderate increase in that of aminoglycosides, paracetamol, theophylline, ibuprofen, lorazepam, alprazolam and oxazepam has been noted. The greatest increase has been found with highly soluble drugs such as thiopentone, verapamil, lignocaine (lidocaine), diazepam and midazolam. Whereas drug absorption does not appear to be altered in obesity, the hepatic metabolism of drugs that are conjugated increases as a function of bodyweight. Therefore the clearance of oxazepam, lorazepam and paracetamol is enhanced. Variable results have been found with regard to oxidation, with no alteration in antipyrine, theophylline or caffeine clearance, but increased metabolism of prednisolone, diazepam and ibuprofen. The systemic elimination of high clearance drugs such as verapamil and lignocaine does not appear to be altered. The marked increases in procainamide and cimetidine renal clearance suggest an alteration in renal tubule transport mechanisms. Digoxin clearance is unaltered. While there are increased concentrations of &agr;1-acid glycoprotein and binding of propranolol, generally drugs bound to albumin show no alteration. Because of the large changes in drug distribution, alteration in dosages may be necessary. For highly lipid-soluble drugs such as theophylline and lignocaine, loading dose should be based on actual bodyweight because of increased volume of distribution. For digoxin, on the other hand, with the normal volume of distribution, dosage should be based on ideal rather than actual bodyweight. While prednisolone clearance is increased, there is an accompanying enhanced sensitivity to adrenosuppression, thus negating the necessity to adjust dosage and emphasising the need for complementary kinetic and dynamic studies. Similarly, although there is an increased volume of distribution of thiopentone, patients appear unusually sensitive. Due to enhanced conjugation, doses of lorazepam, oxazepam and paracetamol should be increased in proportion to total bodyweight.Less information is available concerning the influence of diabetes on drug kinetics. The intramuscular absorption of some antibiotics may be erratic, and in patients with serious infections the intravenous route should be used. The conjugation of phenacetin is impaired in uncontrolled diabetes, but restored with insulin therapy. The oxidation of antipyrine may be altered. There is some evidence to suggest enhanced renal elimination of penicillin, probably secondary to increased glomerular filtration rate. The binding of diazepam, warfarin, lignocaine and phenytoin is decreased, probably due to glycosylation and alterations in plasma proteins. There have been no concomitant kinetic and dynamic studies in diabetic patients, and therefore therapeutic implications of these changes are speculative. Little information is available concerning drug kinetics in less common endocrine disorders. A number of endocrine agents (oral contraceptive steroids, hydrocortisone and growth hormone) may also influence drug kinetics. As well as additional pharmacokinetic information there is a major need for complementary dynamic studies to increase the therapeutic relevance of pharmacokinetic data.
ISSN:0312-5963
出版商:ADIS
年代:1987
数据来源: ADIS
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2. |
Clinical Pharmacokinetics of Factor VIII in Patients with Classic Haemophilia |
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Clinical Pharmacokinetics,
Volume 13,
Issue 6,
1987,
Page 365-380
Andrea Messori,
Giovanni Longo,
Marzia Matucci,
Massimo Morfini,
Pier Luigi Rossi Ferrini,
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摘要:
Studies of Factor VIII pharmacokinetics in haemophiliacs can be classified into 2 groups depending on whether single-dose or multiple-dose Factor VIII curves are used. This review analyses information published so far in both these areas, with particular emphasis on the choice of appropriate models for pharmacokinetic analysis.Single-dose studies of Factor VIII kinetics have previously used a wide variety of methods for pharmacokinetic analysis (empirical methods of Factor VIII level prediction, graphical techniques for semilog analysis, 1-compartment and 2-compartment models). However, Factor VIII poses unique problems to the pharmacokineticist because decay curves can be either monophasic (monoexponential) or biphasic (biexponential) for unknown reasons, and because Factor VIII concentrations are generally subject to significant assay error. Problems of compartmental analysis that occurred in previous studies are highlighted, and a model-independent non-compartmental approach for analysing Factor VIII curves is proposed.To date, fewer data have been published on multiple-dose kinetics of Factor VIII. From a clinical point of view, repeated-dose regimens are most commonly required in patients undergoing surgery and in patients with severe bleeding. A fairly well defined ‘therapeutic window’ of optimal Factor VIII plasma concentrations has been identified, particularly in surgical patients. This fact has spurred research aimed at applying to haemophilia patients the pharmacokinetic dosing methods commonly used for therapeutic monitoring of drugs (e.g. Bayesian method for dosage individualisation). A few papers have already been published in this field, and this review summarises problems encountered by previous investigators, and evaluates comparatively the pharmacokinetic methods used.
ISSN:0312-5963
出版商:ADIS
年代:1987
数据来源: ADIS
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The Relationship Between Antidepressant Response and Tricyclic Antidepressant Plasma ConcentrationsA Retrospective Analysis of the Literature Using Logistic Regression Analysis |
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Clinical Pharmacokinetics,
Volume 13,
Issue 6,
1987,
Page 381-392
Paul J. Perry,
Bruce M. Pfohl,
Sheldon G. Holstad,
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摘要:
The relationship between the antidepressant effect of the tricyclic antidepressants and their plasma concentrations was reviewed. Logistic regression was utilised as an analytical tool to facilitate the evaluation. The currently available literature allowed the construction of 4 tricyclic data sets of sufficient size to warrant statistical analysis. Inspection of the distribution of the data and the logistic regression analyses resulted in several conclusions regarding the existence of ‘therapeutic windows’ for these drugs. Firstly, no relationship between amitriptyline plasma concentrations and therapeutic response was apparent. Secondly, curvilinear relationships were apparent for 2 of the other tricyclic antidepressants studied. The currently recommended therapeutic range of 60 to 150 μg/L for nortriptyline was found to be the range most likely to produce a positive antidepressant effect. Desipramine concentrations between 108 and 158 μg/L were most commonly associated with beneficial therapeutic responses. Finally, a linear relationship was noted for imipramine in which an imipramine therapeutic plasma concentration threshold of 244 μg/L and above was most commonly associated with a beneficial response to the drug.
ISSN:0312-5963
出版商:ADIS
年代:1987
数据来源: ADIS
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4. |
Alterations in the Metabolism of Oestrogens During Treatment with Aminoglutethimide in Breast Cancer PatientsPreliminary Findings |
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Clinical Pharmacokinetics,
Volume 13,
Issue 6,
1987,
Page 393-406
P.E. Lønning,
S. Kvinnsland,
T. Thorsen,
P.M. Ueland,
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摘要:
In this small study, the effect of aminoglutethimide on the disposition of oestrogens in women with advanced breast cancer was investigated using bolus injections of 4-[14C]-oestradiol and 6,7-[3H]-oestrone sulphate, alone or in combination.No alterations in oestrogen disposition were seen after short term (6 hours) aminoglutethimide administration. During long term (3 weeks to 8 months) aminoglutethimide treatment mean 4-[14C]-oestradiol clearance was not changed.14C-Oestrone sulphate AUC was reduced by 43% at a low dose of aminoglutethimide (125mg twice daily) and by 65% at a high dose (250mg 4 times daily) with hydrocortisone acetate 25mg twice daily. The oestrone sulphate terminal elimination rate constant (&lgr;z) was concurrently increased (mean of 46 and 79%, respectively, with the 2 dosage regimens).A possible increase in oestrone sulphate clearance during long term treatment was tested for by injecting 6,7-[3H]-oestrone sulphate. These studies revealed a marked increase (mean 104%) in oestrone sulphate clearance in patients receiving the high dose aminoglutethimide schedule.Following injection of 4-[14C]-oestradiol plus 6,7-[3H]-oestrone sulphate, the fraction of 4-[14C]-oestradiol metabolised to oestrone sulphate was found to be reduced in all patients (mean 13%). A mean increase of 80% in the urinary excretion of14C-oestriol was observed after 4-[14C]-oestradiol administration.Our results, although preliminary, suggest that aminoglutethimide is a potent inducer of aminoglutethimide metabolism, thereby producing a significant reduction in plasma bioavailability of oestrone sulphate. These effects may have a role in the action of aminoglutethimide, a finding which warrants further investigation.
ISSN:0312-5963
出版商:ADIS
年代:1987
数据来源: ADIS
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