摘要:

This article reviews the clinical relevance of pharmacogenetics in cancer chemotherapy, with emphasis on drugs for which genetic differences in enzyme metabolism have been demonstrated to affect patient outcome.About 10% of children with leukaemia are intolerant to mercaptopurine (6-mercaptopurine) because of genetic defects in mercaptopurine inactivation by thiopurineS-methyltransferase. However, mercaptopurine dose intensity, a critical factor for outcome in patients deficient in thiopurineS-methyltransferase, can be maintained by means of thiopurineS-methyltransferase phenotyping or genotyping.Patients with reduced fluorouracil (5-fluorouracil) catabolism are more likely to be exposed to severe toxicity. The measurement of dihydropyrimidine dehydrogenase activity in patients cannot be considered fully predictive, and the role of dihydropyrimidine dehydrogenase gene variants in this syndrome has yet to be clarified.With regard to irinotecan, patients with Gilbert's syndrome phenotype have reduced inactivation of the active topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN-38) caused by a mutation in the UDP-glucuronosyltransferase 1A1 gene promoter. This subset of patients is more likely to be exposed to irinotecan toxicity and could be identified by genotyping for gene promoter variants.Finally, the experience with amonafide represents a model for dose individualisation approaches that use simple phenotypic probes.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Toremifene is a chlorinated triphenylethylene derivative of tamoxifen approved for use in the treatment of patients with metastatic breast cancer. Toremifene is well tolerated in patients, and common adverse effects of this drug include vasomotor symptoms such as hot flashes and vaginal discharge. This compound is administered to patients orally at a dose of 60 mg/day, although alternative methods of administration have been investigated.Oral bioavailability is estimated to be approximately 100%. At steady state, toremifene and its metabolites are highly protein bound (>95%). Toremifene is metabolised in the liver by cytochrome P450 enzymes, and it is eliminated primarily in the faeces following enterohepatic circulation. The half-life of toremifene is approximately 5 days, and steady state is reached by 6 weeks depending on the dose given.The pharmacokinetics of toremifene have been shown to be altered by certain liver conditions, but age and kidney function do not appear to be as significant.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Largely because of their low lipophilicity, cephalosporins poorly penetrate through the blood-brain barrier, achieving relatively low cerebrospinal fluid (CSF) concentrations. However, the minimum bactericidal concentrations (MBCs) of the extended spectrum cephalosporins for common meningeal pathogens are generally low; thus, therapeutic CSF drug concentrations several-fold greater than the MBC can be achieved with currently recommended dosage regimens. However, the effectiveness of cephalosporin therapy is unreliable in patients with meningitis caused by highly penicillin-resistant pneumococci.As in other body sites, the bactericidal activity of cephalosporins in CSF predominantly depends on the time their concentrations exceed the MBC of infecting organisms (t>MBC). Experimental studies show that, for maximal efficacy, t>MBCvalues greater than 90% of the dosage interval are required in meningitis. Such values are usually achieved in humans with currently recommended dosage regimens because the half-lives of cephalosporins are 2- to 3-fold longer in CSF than in serum.Several advanced generation cephalosporins have shown equal efficacy in clinical trials, but only cefotaxime, ceftriaxone and ceftazidime are currently approved for the treatment of patients with bacterial meningitis.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

The current practice for the dose calculation of most anticancer agents is based on body surface area in m2, although lower interpatient variation in pharmacokinetic parameters has been reported with pharmacokinetically guided administration. As chemotherapeutic agents have a narrow therapeutic window, pharmacokinetically guided administration may lead to less toxicity and higher efficacy than administration on the basis of body surface area.Pharmacokinetically guided administration, using parameters such as area under the plasma concentration-time curve (AUC), steady-state plasma drug concentration and drug exposure time above a certain plasma concentration, has been studied for many antineoplastic agents. Assessment of pharmacokinetic profiles allows the characterisation of relationships between pharmacokinetic parameters and efficacy and toxicity. AUC appears to be more closely correlated with pharmacodynamics than does the dose per unit of body surface area.In particular, the AUC-guided administration of carboplatin has been extensively studied, based on the close relationship between the renal clearance of the drug and glomerular filtration rate. Several formulae and limited sampling models have been derived to predict the AUC of carboplatin. The relationship between AUC and pharmacodynamics has also been studied for other anticancer agents, for example fluorouracil, topotecan, etoposide, cisplatin and busulfan, but all less extensively than for carboplatin. The pharmacokinetically guided administration of these agents needs to be investigated further before the use of alternative administration formulae can become standard clinical practice.Prospective studies of pharmacokinetically guided versus surface area−based administration should be performed to validate pharmacokinetic-pharmacodynamic relationships and to facilitate optimal dosage of anticancer agents in the clinic.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

ObjectiveTo investigate the distribution of meloxicam in the human knee joint and to compare it with the inhibition of cyclo-oxygenase (COX) activity in synovial cells.DesignProspective pharmacokinetic study andin vitrolaboratory investigation.Patients and participants42 male and female patients aged 26 to 85 years hospitalised for rheumatic disease and requiring a diagnostic and/or therapeutic knee puncture.MethodsAfter a single oral dose of meloxicam 15mg, synovial fluid and blood samples were collected once per patient at various intervals after administration. Meloxicam concentrations were determined by a validated high performance liquid chromatography assay, protein binding by equilibrium dialysis, and pharmacokinetic parameters were calculated by noncompartmental analysis from the mean drug concentration-time profiles. The inhibitory effect of meloxicam on COX activity was investigated separately in unstimulated or interleukin-1β−stimulated human synovial cells from osteoarthritic patients.ResultsMeloxicam was found in synovial fluid at the earliest sampling time (1 hour). Peak concentrations were reached approximately 6 hours postdose in both plasma (842 µg/L) and synovial fluid (320 µg/L). A plateau was observed after the distribution phase (6 hours), corresponding to a constant ratio of drug concentration between synovial fluid and plasma of about 0.47. This ratio was higher in patients with acute inflammation (0.58) than in those with no inflammation (0.38). Meloxicam was extensively bound to protein, mainly to serum albumin. The area under the drug concentration-time curve (AUC) in plasma was more than 2.5 times that in synovial fluid. The AUC for free meloxicam was similar in plasma and synovial fluid. The 50% inhibitory concentrations (IC50) for basal and stimulated COX activity in human synovial cells were 33.7 nmol/L (11.8 µg/L) and 2.0 nmol/L (0.70 µg/L), respectively. The free concentration of meloxicam in synovial fluid was higher than the IC50for stimulated COX activity from 6 to 36 hours postdose.ConclusionOn the basis of free synovial concentrations and the IC50for stimulated COX activity, meloxicam is expected to have a long duration of action. Inhibition of COX activity is expected to be more marked in inflamed synovium compared with non-inflamed synovium.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS