摘要:

Cimetidine is the first histamine H2-receptor antagonist with wide clinical application. It is a weak base and a highly water-soluble compound which can be measured in biological fluids by a number of high-pressure liquid chromatographic methods.Following intravenous administration, the plasma concentration profile follows multicompartmental characteristics. The total systemic clearance is high (500 to 600 ml/min) and is mainly determined by renal clearance. The volume of distribution (Vd&bgr;or Vdss) is of the order of 1 L/kg and this about equals bodyweight. Elimination half-life is approximately 2 hours.Following oral administration of cimetidine, 2 plasma concentration peaks are frequently observed, probably due to discontinuous absorption in the intestine. The absolute bioavailability in healthy subjects is about 60%. In patients with peptic ulcer disease, bioavailability is around 70%, but the variation is much greater than in healthy subjects. Absorption and clearance of cimetidine are linear after 200 and 800mg doses. Mean steadystate plasma concentrations on a standard 1000mg daily dose are 1.0 μg/ml (range 0.64-1.64 μg/ml) and are reproducible after treatment periods of up to 2 years. When taken with food, the extent of absorption is unaltered, but a delay occurs and only 1 peak in the plasma concentration curve is apparent. Partial gastrectomy (Billroth I, II) causes an increase in systemic availability of cimetidine by an unclear mechanism.Distribution of cimetidine leads to extensive uptake into kidney, lung and muscle tissues. It distributes into the cerebrospinal fluid (CSF) at a ratio of 0.1 to 0.2 compared with plasma. The mean saliva to plasma ratio is 0.2 (range 0.1-0.55). Plasma protein binding is 20%, and there is no relevant effect of changes in binding on the pharmacokinetics of cimetidine. Uptake of cimetidine into red blood cells leads to concentrations equal to those in plasma.Between 50 and 80% of the dose administered intravenously is recovered in urine as unchanged cimetidine. This fraction is less after oral doses, but is independent of the amount of the dose. In ulcer patients, 40% is recovered unchanged in urine after oral administration. Biliary excretion of cimetidine accounts for only 2% of the dose. Metabolites of cimetidine in man represent 25 to 40% of the total elimination, with 1 major metabolite (cimetidine sulphoxide; 10-15%) and 1 minor metabolite (hydroxymethyl cimetidine; 4%). Elimination of cimetidine is accelerated by an average of 15% in the presence of phenobarbitone, due to induction of its metabolism.The clearance of cimetidine is increased in children, due to increased renal elimination mechanisms. With increasing age, the volume of distribution of cimetidine decreases, total plasma clearance decreases as a function of decreasing renal clearance, plasma half-life increases, and the duration of effective plasma concentrations (above 0.5 μg/ml) increases as well.In patients with advanced renal insufficiency, total plasma clearance is reduced from a mean of 500 ml/min to less than 200 ml/min, mainly due to a decrease in renal clearance to 50 ml/min or less. Elimination half-life increases from 2 to 4-5 hours in renal failure patients. The absolute bioavailability in renal failure patients is unchanged or slightly higher compared with controls. A dose reduction for cimetidine is suggested according to the degree of renal impairment, with 400mg daily being recommended in patients with minimal renal function. Cimetidine is dialysable during haemodialysis, but less than 20% of the dose is removed after a single dose, and dose adjustment is seldom necessary.In patients with severe liver cirrhosis, the non-renal clearance of cimetidine is significantly reduced, but bioavailability as well as the duration of effective plasma concentrations (above 0.5 μg/ml) is increased. A dramatic reduction of total plasma clearance and a prolongation of half-life up to 10 times normal may occur when renal failure is associated with chronic liver disease. In intensive care patients, the dosage of cimetidine frequently has to be increased to 1800mg daily to achieve sufficient elevation of gastric pH, and plasma concentrations above 1.5 μg/ml are required in most patients. The mean elimination half-life in these patients is 2.7 hours, but a wide variation in all parameters is observed.Cimetidine crosses the placenta and is detectable in the fetus in considerable concentrations. It also is secreted into breast milk of nursing mothers and may reach the infant in amounts of several milligrams daily.Cimetidine concentrations between 0.5 and 1.0 μg/ml are required to suppress gastric acid secretion under basal conditions or stimulated by pentagastrin or food. Attempts to correlate plasma concentrations of cimetidine or any of the pharmacodynamic parameters to duodenal ulcer healing have so far failed, and thus prediction of therapeutic response from pharmacokinetic data appears disappointing. In cases of overdosage with cimetidine, the pharmacokinetics are unchanged, even with plasma concentrations above 30 μg/ml. Central nervous system side effects such as mental confusion develop in elderly patients and in patients with severe renal or hepatic impairment. In such cases concentrations of cimetidine in the CSF are elevated due to high plasma concentrations and due to a more permeable blood/brain barrier in patients with liver disease.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Antirheumatic drug concentrations have been measured in human synovial fluid and synovial tissue, and provide insights on: (1) extravascular pharmacokinetics; (2) articular pathophysiology; and (3) the factors which modify drug levels in inflamed tissues. Concentrations of free drug in synovial fluid and plasma are the same in all conditions except rheumatoid and infectious arthritis, where the most severely afflicted joints may contain lower synovial fluid drug concentrations. This finding may be relevant to the chronicity and intractability of chronic arthritis. After single-dose therapy and a characteristic ‘equilibration time’, higher concentrations are found in synovial fluid than in plasma - a phenomenon which results from relative drug sequestration across the trans-synovial diffusion barrier away from the organs of elimination. Studies of oral, parenteral, topical and intraarticular antirheumatic drug therapy are reviewed, and recommendations are made for the conduct of future studies.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Metoclopramide is rapidly and well absorbed from the gastrointestinal tract, and in man undergoes variable first-pass metabolism (oral bioavailability 32 to 100%). In man, N-4 sulphate conjugation is an important pathway of metabolism and after oral administration the ratio of free to conjugated metoclopramide in urine correlates with the plasma AUC.The elimination half-life of metoclopramide is dose-dependent after both intravenous and oral administration of single doses between 5 and 20mg. Metabolic profiles in animal species studied are very different from man. The clearance of metoclopramide is reduced in patients with renal failure to approximately 50% of normals and the terminal half-life is prolonged; this is despite the fact that renal clearance of free drug accounts for only 20% of the administered dose in normals.Preliminary studies after ‘high dose’ metoclopramide demonstrate accumulation to high plasma concentrations with linear kinetics, suggesting that current high dose regimens are unnecessarily cumbersome.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

A specific, sensitive, rapid and reproducible analytical method for zimelidine [3-(4-bromophenyl)-N,N-dimethyl-3(3-pyridyl)allylamine] and its biologically active demethylated metabolite, norzimelidine, in human plasma was developed using gas-liquid chromatography (GLC) with loxapine as the internal standard. A good separation of zimelidine and norzimelidine was obtained following derivatisation of norzimelidine with heptafluorobutyric anhydride, the retention times being 6.16 and 10.35 minutes, respectively. The sensitivity of the method is 5 ng/ml for zimelidine and norzimelidine.Plasma concentrations of zimelidine and norzimelidine were determined in 10 healthy volunteers following the administration of a single oral dose of 100mg zimelidine. Zimelidine was rapidly absorbed, giving a mean peak plasma concentration of 103.9 ± 34.8 ng/ml. The mean plasma elimination half-life was 8.4 ± 2.0 hours for zimelidine and 19.4 ± 3.6 hours for norzimelidine. After long term administration of zimelidine (100mg bid for the first week, 100mg tid for the second week and 100mg am and 200mg pm for the third and fourth weeks) to 2 depressed patients, plasma concentrations of norzimelidine were 2 to 4 times higher than those of zimelidine.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Complex segregation analysis of the isoniazid inactivator phenotype has shown the existence of a recessive gene and a multifactorial background. The phenotype is also influenced by age, sex and weight. The relevance of these findings to the grouping of individuals into slow and rapid inactivators is stressed.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The Michaelis-Menten pharmacokinetic parameters Vmaxand Km were calculated for 135 epileptic paediatric patients receiving phenytoin as their only anticonvulsant therapy. Mean Vmaxand Km values were 13.95 mg/kg/day and 6.59 &mgr;g/ml for 0.5 to 3-year-old patients, 10.93 mg/kg/day and 6.82 &mgr;g/ml for the 4 to 6 year age group, 10.05 mg/kg/day and 6.51 &mgr;g/ml for the 7 to 9-year-olds, and 8.25 mg/kg/day and 5.69 &mgr;g/ml for the 10 to 16 year group. Using analysis of variance, the Vmaxvalues were significantly different (p < 0.01) but the Km values were not. Linear regression analysis of Vmaxversusage revealed a significant decline in Vmaxwith age (r = -0.554; p < 0.001). A plot of Kmversusage showed a poor correlation (r = -0.170) and a large amount of variability.Based on this data, the youngest age group would require on average 62% more phenytoin/kg/day than the oldest age group in order to maintain a steady-state phenytoin concentration of 15 &mgr;g/ml. Because of these age-related pharmacokinetic differences, phenytoin dosages may require adjustment as paediatric patients become older.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS