摘要:

Sex-related differences in the disposition of some analgesics, anxiolytics and hypnotics have recently been reported. With certain benzodiazepines, sex has been shown to be a more important determinant of variability in drug disposition than age, while with other benzodiazepines an age-related decline in clearance was more pronounced in men than women. In young healthy adults these sex-related differences in drug disposition were related to the phase of the menstrual cycle, oral contraceptive steroid administration, and variations in plasma concentrations of albumin, &agr;1-acid glycoprotein, free fatty acids and sex hormones. While none of the sex-related differences so far reported necessitates the modification of a therapeutic dosage regimen, it is prudent that future protocols for pharmacokinetic studies should regard age, sex, the menstrual cycle and oral contraceptive steroids as potential sources of variability.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Several studies investigating changes with time in pharmacokinetic parameters of several benzodiazepines are reviewed. At least 3 possibilities (enzyme induction, enzyme inhibition by metabolic products, and unchanged kinetics following long term therapy or high doses) have been postulated in the disposition processes of diazepam. It seems likely that the contradictory results which have been reported can be explained by differences in 1 or several experimental factors influencing the outcome of a study (patient compliance, multiple drug therapy or statistical design). With the 3-hydroxybenzodiazepine lorazepam and the nitro-benzodiazepine nitrazepam, no changes in metabolic activity were observed.Studies with clonazepam in monkeys have confirmed previous observations that reduced metabolic activity during periods of physical inactivity gives rise to circadian fluctuations in steady-state concentrations of the drug. Furthermore, systemic and intrinsic clearances of midazolam were found to be higher following an intravenous dose in the late afternoon than after a morning dose. The protein binding of diazepam is also subject to diurnal variations, and concomitant changes in apparent volume of distribution and clearance have been observed. From the existing data it seems likely that the rate of absorption of several benzodiazepines (including diazepam, clobazam and clorazepate) varies periodically with a 24-hour cycle, pointing to diurnal effects on drug absorption processes.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The methods available for assaying ranitidine in plasma and both the drug and its metabolites in urine are high-performance liquid chromatography and radioimmunoassay. Following oral administration, the absorption of ranitidine in normal individuals has been found to be rapid, with peak plasma concentrations occurring at 1 to 3 hours. Peak plasma concentrations bear a constant relationship to dose, but vary widely between individuals. The bioavailability of ranitidine after oral administration is approximately 50% due to presystemic hepatic metabolism. Plasma protein binding of ranitidine is approximately 15% and the apparent volume of distribution is greater than body volume. Ranitidine penetrates very poorly into the cerebrospinal fluid but is concentrated into breast milk.After intravenous administration, plasma concentrations decay in a biexponential manner. The elimination half-life is almost 2 hours and is somewhat longer after oral administration. Plasma clearance is approximately 600 ml/min of which most is renal clearance. Elimination of ranitidine is not dose-dependent. Hepatic metabolism is the other major route of elimination and there may be some enterohepatic recycling of the drug.Food has no effect on the kinetics of ranitidine but concurrent administration of antacids reduces its absorption. Renal disease causes an increase in ranitidine plasma concentrations through reduced clearance and possibly increased bioavailability. Chronic liver disease causes an increase in the bioavailability of ranitidine and some reduction in clearance. In the elderly, there is a reduction in clearance and prolongation of the elimination half-life but little effect on bioavailability. There is a relationship between plasma concentrations of ranitidine and suppression of gastric acid production but wide interindividual variability.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

In recent years there has been a renewal of interest in chloramphenicol, predominantly because of the emergence of ampicillin-resistantHaemophilus influenzae,the leading cause of bacterial meningitis in infants and children. Three preparations of chloramphenicol are most commonly used in clinical practice: a crystalline powder for oral administration, a palmitate ester for oral administration as a suspension, and a succinate ester for parenteral administration. Both esters are inactive, requiring hydrolysis to chloramphenicol for antibacterial activity. The palmitate ester is hydrolysed in the small intestine to active chloramphenicol prior to absorption. Chloramphenicol succinate acts as a prodrug, being converted to active chloramphenicol while it is circulating in the body.Various assays have been developed to determine the concentration of chloramphenicol in biological fluids. Of these, high-performance liquid chromatographic and radioenzymatic assays are accurate, precise, specific, and have excellent sensitivities for chloramphenicol. They are rapid and have made therapeutic drug monitoring practical for chloramphenicol.The bioavailability of oral crystalline chloramphenicol and chloramphenicol palmitate is approximately 80%. The time for peak plasma concentrations is dependent on particle size and correlates within vitrodissolution and deaggregation rates. The bioavailability of chloramphenicol after intravenous administration of the succinate ester averages approximately 70%, but the range is quite variable. Incomplete bioavailability is the result of renal excretion of unchanged chloramphenicol succinate prior to it being hydrolysed to active chloramphenicol. Plasma protein binding of chloramphenicol is approximately 60% in healthy adults. The drug is extensively distributed to many tissues and body fluids, including cerebrospinal fluid and breast milk, and it crosses the placenta. Reported mean values for the apparent volume of distribution range from 0.6 to 1.0 L/kg. Most of a chloramphenicol dose is metabolised by the liver to inactive products, the chief metabolite being a glucuronide conjugate; only 5 to 15% of chloramphenicol is excreted unchanged in the urine. The elimination half-life is approximately 4 hours. Inaccurate determinations of the pharmacokinetic parameters may result by incorrectly assuming rapid and complete hydrolysis of chloramphenicol succinate.The pharmacokinetics of chloramphenicol succinate have been described by a 2-compartment model. The reported values for the apparent volume of distribution range from 0.2 to 3.1 L/kg. Chloramphenicol succinate is metabolised (hydrolysed) by esterases in the body to active chloramphenicol. Approximately 30% of the succinate ester is excreted unchanged in the urine, with a reported range of 6 to 80%.Plasma protein binding and the clearance of chloramphenicol are reduced and the elimination half-life prolonged in patients with liver disease, but the elimination half-life is not significantly changed by renal dysfunction. Serum chloramphenicol concentrations are higher in patients with renal impairment after the administration of intravenous chloramphenicol succinate, but not oral chloramphenicol; this is due to a reduction in renal excretion of the succinate ester, resulting in increased bioavailability of active chloramphenicol. Plasma protein binding is decreased in uraemic patients, apparently due to displacement by unidentified substances. In premature and newborn infants, oral absorption of chloramphenicol after administration of the palmitate ester is slow and unreliable. The elimination of both chloramphenicol and chloramphenicol succinate is decreased in these infants as a result of immature hepatic and renal function. Plasma protein binding is also lower in newborn infants than in children and adults. The elimination of chloramphenicol may also be markedly impaired in patients in shock.Chloramphenicol impairs the metabolism of tolbutamide, chlorpropamide, cyclophosphamide, phenytoin, phenobarbitone and dicoumarol. Paracetamol (acetaminophen) has been reported to decrease the metabolism of chloramphenicol. Phenytoin and phenobarbitone hasten the elimination of chloramphenicol, most likely due to enzyme induction. Mannitol, ethacrynic acid, hydrochlorothiazide and clopamide increase the renal excretion of chloramphenicol, whereas frusemide (furosemide) decreases its renal excretion.Peak chloramphenicol concentrations of 10 to 20 &mgr;g/ml and trough concentrations of 5 to 10 &mgr;g/ml are generally desirable for most infections. Therapeutic concentrations depend on the sensitivity of the specific offending organism, in addition to the type and severity of infection. Concentration-dependent bone marrow suppression has been associated with sustained peak serum concentrations ≥ 25 &mgr;g/ml and trough concentrations ≥ 10 &mgr;g/ml. The ‘grey syndrome’ has been associated with chloramphenicol concentrations of ≥ 40 &mgr;g/ml.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Sodium nitroprusside decomposes within a few minutes after intravenous infusion to form metabolites which are pharmacologically inactive but toxicologically important. Free cyanide, which represents 44% w/w of the sodium nitroprusside molar mass, is formed and must be detoxified in the body into thiocyanate using thiosulphate as substrate.Nitroprusside penetrates cell membranes slowly. At therapeutic dose levels its distribution is probably mainly extracellular. Contact with the sulfhydryl groups in the cell walls, however, immediately initiates breakdown of the molecule. Sodium nitroprusside taken orally is not absorbed from the gastrointestinal tract to any appreciable extent.Cyanides in the body form prussic acid, which can rapidly penetrate mucous and cell membranes. In the blood, about 99% of the prussic acid binds to the methaemoglobin of erythrocytes. At normal physiological levels, however, the total body methaemoglobin of an adult human can only bind about 10mg of prussic acid; this is a small fraction of the amounts usually infused therapeutically as sodium nitroprusside.The endogenous detoxification of prussic acid exhibits zero-order kinetics. The limiting factor is a sulphur donor, principally thiosulphate, which is available in the body in only limited amounts. The rate of spontaneous detoxification of prussic acid in humans is only about 1 &mgr;g/kg/min, corresponding to a sodium nitroprusside infusion of about 2 &mgr;g/kg/min. This dose limit set by the prussic acid toxicity of sodium nitroprusside can, however, be increased considerably by simultaneous infusion of thiosulphate. A lack of thiosulphate can be detected early by a rise of the prussic acid concentration in the erythrocytes.Thiosulphate taken orally is not absorbed by the body. After intravenous infusion, its serum half-life is about 15 minutes. Most of the thiosulphate is oxidised to sulphate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys.Thiocyanate taken orally is completely absorbed by the body. In healthy persons its volume of distribution is approximately 0.25 L/kg and the serum half-life about 3 days; elimination is mainly renal. Thiocyanate toxicity does not represent a serious therapeutic problem with intravenous infusion of sodium nitroprusside.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Plasma concentrations of primidone and its metabolite phenobarbitone were monitored in 9 pregnant epileptic patients treated with primidone (and in 3 cases other antiepileptic drugs) given at constant doses throughout pregnancy and the puerperium. Phenobarbitone plasma concentrations were monitored in another 6 patients given phenobarbitone itself. A trend towards increasing primidone plasma concentrations during the second quarter of pregnancy was evident in all patients, with a concomitant significant decrease in primidone-derived phenobarbitone plasma concentrations. A trend towards a lowering of plasma concentrations of phenobarbitone administered as such was confirmed.These results suggest the usefulness of a careful monitoring of primidone and primidone-derived phenobarbitone during pregnancy and the puerperium. Discrepancies of findings with primidone and phenobarbitone are discussed in view of the possible mechanism involved.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Fifteen depressed elderly patients (14 female, 1 male; mean age 85 years) received a single oral dose of amitriptyline. The concentration of amitriptyline plus nortriptyline in a blood sample taken 24 hours later was used to predict by means of a nomogram the amitriptyline dosage required for each patient. Each dose was selected to produce steadystate amitriptyline plus nortriptyline concentrations close to 140 &mgr;g/L. The daily dosage ranged from 20 to 100mg (mean 62mg).Patients received the individually calculated dose each night, and weekly blood samples were obtained for drug analysis. At 2 weeks, mean amitriptyline plus nortriptyline concentrations were 118 ± 21 &mgr;g/L. Eight of the patients were studied for a further 2 weeks and the mean amitriptyline plus nortriptyline concentration was then 111 + 19 &mgr;g/L.The dose prediction test is easy to use and ensures each patient receives an adequate but safer dose of amitriptyline than might otherwise be prescribed routinely.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS