ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Heparin binds reversibly to its target sites of action, antithrombin and the other serine proteases involved in coagulation, especially activated factor X. It also binds to other plasma proteins, including fibrinogen, plasmin, albumin, and lipases. The volume of distribution of heparin is then, under most circumstances, limited to the plasma volume. Heparin has a very short half-life, about 1.5 hours, which is dose-dependent and varies with the assay method employed for its measurement. It is not eliminated enzymatically nor by glomerular filtration or renal tubular secretion. In all likelihood, the anticoagulant is transferred to reticuloendothelial cells, which may also provide the means for its degradation.Many of the difficulties inherent in assessing the kinetic properties of heparin, as well as its clinical efficacy, may be attributed to: (1) its molecular heterogeneity; (2) its wide spectrum of binding sites and their respective kinetic properties and dissociation constants; (3) differences among methods for measuring heparin effect and concentration; (4) the dose dependence of the drug's half-life; (5) variation in patient response to heparin; (6) the specific cation associated with it; and (7) the presence of hypercoagulation syndromes associated with deficits of antithrombin. Neither renal nor hepatic disease, nor the biological tissues from which heparins are extracted commercially, seem to influence the drug's kinetic properties as much as variations in clearance and response to heparin among individual patients.Many comparisons among available studies are difficult because of the wide variation in the assay methods employed in them. It would appear that optimum therapy with heparin can be achieved only when the individual patient's response to, and rate of elimination of, heparin are taken into account concurrently.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

Despite extensive use of diuretics, for only a few have their pharmacokinetics been evaluated.Bendroflumethiazide is completely absorbed and uptake from the gastrointestinal tract is not changed by food. Plasma half-life is about 3h. Apparent volume of distribution averages 1.5L/kg. Up to two thirds of the drug is eliminated via non-renal routes.Hydrochlorothiazide is 65% absorbed in healthy fasting subjects and 75% absorbed when given with food. The increased uptake appears to be caused by decreased gastric emptying rate. Absorption is impaired in patients who have undergone intestinal shunt surgery and in some patients with cardiac failure. Plasma half-life averages 10h in subjects with normal renal function. It is prolonged in renal failure as the drug is mainly eliminated via the kidneys in unchanged form.The bioavailability of hydroflumethiazide is at least 50%. Elimination half-life is about 17h in normal subjects and 10h in patients with cardiac failure. The drug is largely eliminated unchanged in the urine.The half-life of polythiazide is approximately 26h. About 20% of an oral dose is cleared via the kidneys.Chlorthalidone is 65% absorbed. Up to 75% of a dose is bound to plasma proteins and extensively to blood cells. Only 1.4% of the total amount of the drug in blood is found in plasma. Plasma half-life averages 40 to 65h. Apparent volume of distribution is close to 300L. This diuretic is mainly eliminated in the urine, although it is metabolised to some extent.Bumetanide is completely absorbed. Up to 96% is bound to plasma proteins. Apparent volume of distribution ranges from 12 to 35L. Plasma half-life is 1.2 to 1.5h in healthy subjects and does not appear to be prolonged in renal failure. Renal and non-renal clearance contributes equally to its elimination.The uptake of frusemide (furosemide) from the gastrointestinal tract is about 65% and is decreased in uraemia and nephrosis. Protein binding is 96 to 98% and is diminished in nephrosis. Plasma half-life is approximately 50 minutes in healthy subjects and is prolonged about 3 times in renal failure. Apparent volume of distribution (Vd&bgr;) ranges from 14 to 17L. Urinary excretion and non-renal elimination contribute almost equally to plasma clearance.The uptake of amiloride is at least 50% and is diminished when given with food. Plasma half-life averages 10h. Amiloride is essentially eliminated unchanged in the urine.Spironolactone and potassium-canrenoate are both metabolised to canrenone which mainly exerts the renal effects of the drugs. The uptake from the gastrointestinal tract is at least 70 and 100% respectively. The protein binding of canrenone averages 98%. The half-life of canrenone is 18 to 20h after doses of 100 to 400mg. Canrenone is eliminated as metabolites via the urine and the bile.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The plasma binding of basic (cationic) drugs differs from that of the more completely studied acidic drugs. Basic drugs associate with a number of plasma constituents. &agr;1-Acid glycoprotein, lipoprotein, and albumin all appear to play an important role in the binding of most of these drugs. Acidic drugs bind largely to albumin. The variation in plasma albumin is relatively narrow and is almost always in the direction of decreased concentrations. &agr;1-Acid glycoprotein and lipoproteins show large fluctuations due both to physiological and pathological conditions. Decreases and increases in concentration have been observed. Associated with these changes in binding proteins, both decreases and increases in plasma binding of basic drugs have been recorded. Increased binding with disease appears to be virtually unique to basic drugs.The implications of these newly described disease-induced increases in plasma binding have yet to be explored. With the limited information in hand the following consequences are predicted. Increased binding will tend to decrease the volume of distribution of total (bound plus free) drug. The clearance will be unchanged or decreased depending upon the initial clearance of the drug and the avidity of the protein binding. As the half-life depends upon both clearance and volume of distribution, changes in it will be variable, depending upon changes in these two parameters. It is predicted that the area under the free drug plasma concentration-time curve will decrease with increasing binding after an intravenous dose while it will be unchanged after an oral dose.The relationship of total drug plasma concentration to free drug concentration will change with changes in binding. Thus plasma concentration monitoring of drug therapy by use of total drug concentrations will be inaccurate in situations in which large variations in binding occur. Misinterpretations of both therapeutic monitoring and pharmacokinetic studies in disease states with altered binding are likely unless these changes are appreciated.

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

摘要:

The pharmacokinetics of sulphamethizole, sulphamethoxazole. sulphadiazine, sulphapyridine and sulphadimidine have been studied in man. Renal clearance values of the metabolite N4-acetylsulphonamide are 6 to 20 times higher than those of the corresponding parent compound. The renal clearance of sulphonamides is dependent on the urine flow.N4-Acetylsulphonamide concentration-time profiles for plasma and urine have been constructed for the sulphonamides. The percentage N4-acetylsulphonamide-time profiles for plasma are excellent tools for establishing the acetylator phenotype, while those constructed from urine samples are less useful. Evidence is obtained that sulphadimidine is metabolically processed by 2 different isoenzymes, while sulphadiazine, sulphapyridine and sulphamethoxazole are processed by I acetylating isoenzyme. Sulphamethizole is acetylated to very little extent.

ISSN:0312-5963    

出版商:ADIS    

年代:1980

数据来源: ADIS

摘要:

The pharmacokinetics of gentamicin were evaluated in 50 children and adolescents during a multiple dose course of therapy. Parameters of a 2-compartment pharmacokinetic model were derived from serial serum concentrations and urinary excretion rates measured for up to 11 days following the last dose of gentamicin administered to 10 of these patients. These parameters were used to simulate changes in serum concentrations and half-lives that would occur during a standard 6-hour dosing interval with continuous dosing.The data indicated that the half-life for decline in serum concentrations after the first dose was 76 ± 8% of the half-life at steady-state, and that the half-life after the fourth dose exceeded 90% of the steady-state half-life. These underestimations of the steady-state serum half-life were incorporated into a 1-compartment model to simulate steady-state peak and nadir serum concentrations by using pharmacokinetic parameters measured after the first dose of gentamicin administered to 40 patients. Steady-state serum concentrations predicted by the true 1-compartment model and by the adjusted model were compared with concentrations measured at steady-state. The concentrations predicted by the former model were significantly different from and consistently less than measured concentrations. Concentrations predicted by the adjusted model were not significantly different from concentrations measured at steady-state.These data indicate that the new model offers a simple and more accurate method of simulating steady-state concentrations from pharmacokinetic parameters measured after initial doses of gentamicin and offers an improved model for individualising therapy.

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