摘要:

The absorption of methotrexate following intramuscular injection and oral administration of small doses (< 30mg/m2) is rapid and complete, whereas with oral doses in excess of 80mg/m2absorption is less than complete. Pretreatment with oral neomycin decreases and with kanamycin increases the gastrointestinal absorption of oral methotrexate.The plasma disposition of methotrexate is multiexponential. Due to differences in sampling schedule and assay methods, widely varying estimates of elimination half-life (t1/2&bgr;of 6 to 69 hours of methotrexate have been reported. The long half-life may either be due to enterohepatic circulation of methotrexate and/or its metabolites or a slow elimination of dihydrofolate reductase (DHFR) bound methotrexate. The plasma clearance of methotrexate following small clinical doses is about 80ml/min, but may become saturated at high doses (20g). During high dose infusions, the peak plasma level is proportional to doses up to 200mg/kg.Methotrexate is transported across cellular membranes via a carrier-mediated active type process. At high concentrations, when the carrier route is saturated, passive diffusion assumes greater importance.Methotrexate is not highly bound to plasma proteins (˜50%). However, being highly ionised at physiological pH, the drug does not accumulate in the cerebrospinal fluid to any appreciable extent, necessitating intrathecal administration in the treatment of cerebral and meningeal metastases.Renal excretion is the major route of elimination for methotrexate (˜80%); the drug being actively secreted in the renal tubule by the general organic acid transport system. Hence, the renal clearance of methotrexate is decreased by the concomitant administration of organic acids, such as salicylate. The renal clearance of methotrexate is correlated with endogenous creatinine clearance which may provide a guideline to dosage adjustments according to renal function and age. With high dose methotrexate, routine administration of fluid and/or bicarbonate is recommended to prevent intratubular precipitation of the drug.Biliary excretion of methotrexate constitutes less than 10% of the administered dose. Other extrarenal routes of excretion such as secretion into human breast milk and saliva are negligible.About a third of an oral dose of methotrexate is metabolised by intestinal bacteria during absorption. The major metabolite is 4-amino-4-deoxy-N10-methylpteroic acid. Small amounts (< 11%) of 7-hydroxymethotrexate have also been found in urine of patients receiving high dose methotrexate therapy. Except for the poly-&ggr;-glutamates, all of the reported metabolites are less effective than methotrexate as an inhibitor of dihydrofolate reductase. As determined by inhibition of DNA synthesis, normal tissues are sensitive to low levels of methotrexate (˜ 10-8M). Furthermore, toxicity with methotrexate is related to duration of exposure as well as to the dose or plasma concentration.Impurities, such as methopterin and other byproducts of the synthetic process have been found in commercial parenteral dosage forms of methotrexate. The clinical significance of these impurities requires further study.For a phase-specific chemotherapeutic agent such as methotrexate, effective plasma levels of the drug should be maintained during the proliferative phase of the tumour cell cycle to achieve a maximum cytotoxic effect. Monitoring the plasma level of methotrexate, particularly during high dose therapy, may provide information regarding impending toxicity and the need for extended citrovorum factor rescue.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Psychotic patients treated with identical doses of antipsychotic drugs have been shown to have great interindividual differences in their steady state plasma concentration. Therefore, monitoring treatment by dosage adjustment alone is of little value. If antipsychotic blood levels can be related to clinical response then their routine measurement may well result in well defined guidelines to individualised optimal dosage.Despite the considerable effort expended in this field and the many interesting testable hypotheses generated, little substantive evidence for an acceptable plasma level monitoring guide has been reported to date. Work on metabolite level profiles, intra- and extracellular drug concentration differences, more detailed clinical rating scales, and improved experimental design, all show great promise for the future. Investigation of the pharmacokinetics and the elucidation of the often complex metabolic pathways of individual antipsychotic drugs are generating the data base required for the rational pharmacotherapy of these most severely ill patients.Until more data are available, routine monitoring of antipsychotic drug plasma levels remains of research interest.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

The observation that drug concentrations in saliva are often proportional to the concentrations in plasma has led to the suggestion that in therapeutic drug monitoring, or in pharmacokinetic studies in general, saliva might be substituted for plasma. Saliva can be collected by non-invasive techniques, generally following the stimulation of salivary flow by chewing on some semi-solid material or by spraying citric acid on the tongue.There is evidence that many organic compounds enter saliva by a passive diffusion process, where lipid solubility and the degree of ionisation — dependent on plasma and salivary pH — are important factors. In addition, it has been shown for some drugs that their concentration in saliva equals the free or protein-unbound concentration in plasma, which is an advantage because drug plasma concentrations generally represent both bound and unbound drug. Lithium is the most well-known example of a drug that is actively secreted in saliva, but active transport mechanisms have also been proposed for organic drugs since discrepancies and time dependencies in the saliva/plasma concentration ratios have been reported, especially in single dose studies (e.g. theophylline).If saliva is to be used in therapeutic monitoring then the saliva to plasma concentration ratio should be constant over a wide plasma concentration range. For the anticonvulsant drugs phenytoin, primidone, ethosuximide and carbamazepine, the existence of a consistent correlation between their concentrations in saliva and plasma has been established under steady state conditions. Saliva concentrations appear to be the same as the protein unbound concentrations in plasma, and the S/P ratio is not influenced by concurrent therapy with other anticonvulsants. For phenobarbitone, a larger variability in the S/P ratio has been observed, probably due to the fact that its salivary concentration is dependent on salivary pH.For digoxin, a substantial interindividual variation in the S/P ratio has been found in patients on long-term therapy, which makes the use of saliva for digoxin monitoring doubtful. Due to the substantial inter- and intraindividual variation in the S/P ratio of procainamide in patients on long-term therapy it is impossible to predict its plasma concentration on the basis of saliva concentrations. However, clinically, the saliva concentration of procainamide may be relevant, since this concentration and the pharmacological effect are correlated. The value of salivary drug concentration measurements in monitoring quinidine therapy is still unclear, due to the lack of information concerning the salivary excretion of quinidine in patients on long-term therapy.Salivary concentration measurements are of limited value in monitoring theophylline therapy since this drug shows a strong time-dependency in the S/P ratio, resulting in large inter- and intraindividual variations especially during the absorption phase in single oral and rectal dose studies. A substantial interindividual variability also occurs in the S/P ratio with lithium. However, within an individual subject this value remains constant over a long period. Therefore once the S/P ratio has been established, measurement of saliva concentrations provides all information necessary for rational dosage adjustment in lithium therapy. Due to the lack of information concerning the salivary excretion of salicylate under steady state conditions and in the therapeutic concentration range, the value of saliva salicylate concentrations in therapeutic monitoring remains unclear.For'antipyrine, S/P values in the range of about I are usually observed. Therefore, saliva data permit the calculation of pharmacokinetic parameters like plasma half-life, apparent volume of distribution and total body clearance in antipyrine studies. That salivary drug concentration measurements may be a useful approach to acetylation phenotyping has been illustrated with drugs like sulphasalazine and isoniazid. The S/P ratio for a number of other drugs has been summarised but these are probably not of great value for therapeutic drug monitoring purposes.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

The renal haemodynamics of a particular patient may affect the pharmacological and pharmacokinetic properties of various drugs. For example, diminution in renal haemodynamics may lead to fluid retention and an increase in the volume of distribution of the drug. Also, fluid retention causes a decrease in plasma protein concentration which for certain drugs can result in altered protein binding and consequently increased proportion of unbound drug and a more marked pharmacological response.The clearance of many drugs and/or metabolites also in influenced by the state of renal haemodynamics. In states of poor renal perfusion, drugs which are mainly eliminated through renal mechanisms have a reduced rate of clearance. The resultant prolongation of the elimination half-life of the drug may increase its toxicity. Knowledge of the renal haemodynamic state, therefore, should be considered in determining the dose and frequency of drug administration.Studies in man have shown that both renal blood flow and glomerular filtration rate are reduced below normal in states of congestive heart failure, liver disorders such as cirrhosis, and, of course, acute and chronic renal failure. In these pathological states, severe cortical vasoconstriction may be present and primarily account for the impairment in renal haemodynamics and alterations in drug kinetics and action.Not only can the renal haemodynamic state affect the actions of drugs, but also exogenous administration of certain drugs can alter renal haemodynamics. The kidney's response to these agents is influenced by pathological and physiological factors, including sodium balance and the ability of the kidney to autoregulate its blood flow. In general, however, renal haemodynamics are diminished by renal vasoconstrictors and improved by renal vasodilators. The altered state of renal haemodynamics in turn may modify the pharmacological and pharmacokinetic properties of other drugs present in the body.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

摘要:

Diazepam is still one of the most used of the benzodiazepine group of drugs. Extensive studies over 10 years have defined a fairly complete profile of its kinetics. Minor aspects relating to patterns of its metabolism and excretion in certain age groups and in some disease states remain to be described quantitatively. However, there is more than sufficient kinetic information available for the requirements of good clinical practice.For optimum clinical benefit with minimum side-effects the following kinetic properties should be borne in mind: (a) there is a large interindividual variation (up to 30-fold) in dose/blood level ratios, especially when treatment is short-term; (b) the elimination half-life is prolonged in the elderly and the newborn and in some cases of liver disease; (c) there is accumulation of the active N-desmethylated metabolite during long-term treatment; and (d) administration of diazepam to pregnant women leads to rapid distribution from the maternal to fetal compartment: accumulation of both diazepam and desmethyldiazepam could cause prolonged sedation in the newborn. As there does not appear to be any clear relationship between the concentration of diazepam in the plasma and clinical effect, measurement of blood levels, other than for research purposes, is unnecessary.Based on kinetic data, a single administration of diazepam at night should be adequate for hypnotic and anxiolytic effects in most patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1978

数据来源: ADIS