摘要:

Cyclosporin (cyclosporin A) has been used as an immunosuppressive agent after organ transplantation for more than 15 years. The bioavailability of cyclosporin in its conventional oral formulation ‘Sandimmun’ displays considerable inter- and intra-patient variability. Absorption is also bile dependent. Recently, a new galenic formulation of cyclosporin was introduced, ‘Neoral’, which is a water-free microemulsion of cyclosporin. The microemulsion creates micelles which are absorbed in the small bowel without the presence of bile.Pharmacokinetic studies in healthy volunteers clearly demonstrate an increased bioavailability of the microemulsion formulation of cyclosporin, measured as an increase in maximum drug concentration (Cmax) and area under the drug concentration-time curve, and a reduced time to Cmax. These findings have been confirmed in kidney, liver and heart transplant recipients. With the microemulsion formulation, an improved prediction of cyclosporin concentrations has probably attributed to the decrease found in the variability of cyclosporin absorption. This could probably enable easier and more reliable monitoring of cyclosporin concentrations after transplantation.So far, data on the effects of conversion from the conventional to the microemulsion formulation of cyclosporin are only available in a limited number of patients and with a limited follow-up period. The main questions are related to what the long term consequences of the improved bioavailability of the microemulsion formulation will be. Further long term studies are needed in order to answer these questions.In the present review, we report on the pharmacokinetic properties of, and on clinical experience after solid organ and bone marrow transplantation with, the microemulsion formulation.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Low-dose pulse methotrexate has emerged as one of the most frequently used slow-acting, symptom-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA) because of its favourable risk-benefit profile.Methotrexate is a weak bicarboxylic acid structurally related to folic acid. The most widely used methods for the analysis of methotrexate are immunoassays, particularly fluorescence polarisation immunoassay. After oral administration, the drug is rapidly but incompletely absorbed. Since food does not significantly affect the bioavailability of oral methotrexate in adult patients, the drug may be taken regardless of meals. There is a marked interindividual variability in the extent of absorption of oral methotrexate. Conversely, the intraindividual variability is moderate even over a long time period. Intramuscular and subcutaneous injections of methotrexate result in comparable pharmacokinetics, suggesting that these routes of administration are interchangeable.A mean protein binding to serum albumin of 42 to 57% is usually reported. Again, the unbound fraction exhibits a large interindividual variability. The steady-state volume of distribution is approximately 1 L/kg. Methotrexate distributes to extravascular compartments, including synovial fluid, and to different tissues, especially kidney, liver and joint tissues. Finally, the drug is transported into cells, mainly by a carrier-mediated active transport process.Methotrexate is partly oxidised by hepatic aldehyde oxidase to 7-hydroxy-methotrexate. This main, circulating metabolite is over 90% bound to serum albumin. Both methotrexate and 7-hydroxy-methotrexate may be converted to polyglutamyl derivatives which are selectively retained in cells. Methotrexate is mainly excreted by the kidney as intact drug regardless of the route of administration. The drug is filtered by the glomeruli, and then undergoes both secretion and reabsorption processes within the tubule. These processes are differentially saturable, resulting in possible nonlinear elimination pharmacokinetics. The usually reported mean values for the elimination half-life and the total body clearance of methotrexate are 5 to 8 hours and 4.8 to 7.8 L/h, respectively. A positive correlation between methotrexate clearance and creatinine clearance has been found by some authors.Finally, the pharmacokinetics of low-dose methotrexate appears to be highly variable and largely unpredictable even in patients with normal renal and hepatic function. Furthermore, studies in patients with juvenile rheumatoid arthritis provide evidence of age-dependent pharmacokinetics of the drug. These features must be considered when judging the individual clinical response to methotrexate therapy.Various drugs currently used in RA may interact with methotrexate. Aspirin might affect methotrexate disposition to a greater extent than other nonsteroidal anti-inflammatory drugs without causing greater toxicity. Corticosteroids do not interfere with the pharmacokinetics of methotrexate, whereas chloroquine may reduce the gastrointestinal absorption of the drug. Folates, especially folic acid, have been shown to reduce the adverse effects of methotrexate without compromising its efficacy in RA. Finally, both trimethoprim-sulfamethoxazole (cotrimoxazole) and probenecid lead to increased toxicity of methotrexate, and hence should be avoided in patients receiving these drugs.A relationship between oral dosage and efficacy has been found in the range 5 to 20mg methotrexate weekly. The plateau of efficacy is attained at approxi-mately 10 mg/m2/week in most patients. No clear relationship between pharma-cokinetic parameters and clinical response has been demonstrated. Overall, the dosage must be individualised because of interindividual variability in the dose-response curve. This variability is probably related, at least in part, to the wide interindividual variability in the disposition of the drug.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Determination of the concentration of drugs and metabolites in biological fluids or matrices other than blood or urine (most commonly used in laboratory testing) may be of interest in certain areas of drug concentration monitoring.Saliva is the only fluid which can be used successfully as a substitute for blood in therapeutic drug monitoring, while an individual's past history of medication, compliance and drug abuse, can be obtained from drug analysis of the hair or nails. Drug concentrations in the bile and faeces can account for excretion of drugs and metabolites other than by the renal route. Furthermore, it is important that certain matrices (tears, nails, cerebrospinal fluid, bronchial secretions, peritoneal fluid and interstitial fluid) are analysed, as these may reveal the presence of a drug at the site of action; others (fetal blood, amniotic fluid and breast milk) are useful for determining fetal and perinatal exposure to drugs. Finally, drug monitoring in fluids such as cervical mucus and seminal fluid can be associated with morpho-physiological modifications and genotoxic effects.Drug concentration measurement in nonconventional matrices and fluids, although sometimes expensive and difficult to carry out, should therefore be considered for inclusion in studies of the pharmacokinetics and pharmacodynamics of new drugs.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Diuretic resistance is encountered in a number of disease states, such as chronic renal failure, nephrotic syndrome, congestive heart failure (CHF) and cirrhosis. Diuretic stratagems which produce sequential nephron segment blockade, and thus a synergistic diuretic response, are frequently necessary and are regularly employed in these conditions. Pharmacokinetic determinants of diuretic response, including dose administered, absolute bioavailability, and tubular transport capacity and transport rate, are reviewed here. Pharmacodynamic factors are perhaps more important to overall response, and often result in modification of the dose-response relationship; these are also reviewed here.Stratagems used to maximise the diuretic response to loop diuretics include correcting abnormal haemodynamic parameters, utilising larger doses or constant intravenous infusions, and using albumin as a vehicle to deliver the loop diuretic to the site of tubular secretion. If these measures fail, then diuretic combinations are useful. Perhaps the most effective is the combination of metolazone (a thiazidetype diuretic) and a loop diuretic. The rationale for and use of various diuretic combinations, with particular emphasis on the metolazone-loop diuretic combination, is reviewed here and applied to the major disease states associated with diuretic resistance.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS