Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1of the first cycle with a validated high performance liquid chromatography method, and the main pharmacokinetic variables were determined. Follow-up of all patients was extended up to 5 years after the end of adjuvant chemotherapy, and DFS was recorded. Univariate and multivariate analyses were conducted to evaluate any correlation among 5-FU pharmacokinetics, clinical and pathologic variables, and DFS. Results: The area under the time/concentration curve (AUC) of 5-FU was significantly lower in 58 subjects who recurred (7.5 F 2.9 h  mg/L) with respect to other patients (9.3 F 4.1 h  mg/L). Furthermore, AUC values lower than 8.4 h  mg/L together with lymph node involvement and the interruption of treatment or reduction of doses were identified as risk factors at univariate analysis. The completion of 6 cycles of adjuvant treatment without dosage modifications was the only independent risk factor at multivariate analysis, despite a trend toward significance for 5-FU AUC values (cutoff value, 8.4 hÂmg/L) was observed (P = 0.06). Conclusions: Pharmacokinetics of 5-FU should be regarded as an important factor for predicting disease recurrence in colorectal cancers.
c.3435CC patients require higher clozapine doses to achieve the same plasma concentrations as CT or TT patients, and ABCB1 genotyping should be considered as a novel strategy that should improve drug use.
After the rapid development of new classes of antineoplastic drugs, research activities have focused their efforts to the identification of predictive markers of drug activity and tolerability. Irinotecan (CPT-11) may induce severe toxicities (diarrhea, neutropenia) that limit its clinical use, but the increasing knowledge of its pharmacokinetics offered a potential approach to treatment optimization. Pharmacokinetics, the first area of investigation, has identified markers such as biliary index, the relative extent of conversion and the glucuronidation ratio, which are capable to define the risk for severe adverse effects. Because of the existence of some issues concerning the adoption of pharmacokinetic strategies to optimize CPT-11 dose and schedule, analyses of genetic polymorphisms seemed to offer a more reliable and safer approach for the identification of patients at risk than pharmacokinetics. In this view, the uridine diphosphate glucuronosil transferase isoform 1A1 (UGT1A1) was associated with significant changes in disposition of CPT-11 and its metabolites, and consequently with treatment-induced toxicities. However, the complex pharmacokinetics of irinotecan and the involvement of several enzymes other than UGT (i.e., carboxyl estherases, CYP450 isoforms), and transmembrane transporters (ABCB1, ABCC1, ABCG2, SLCO1B1) make difficult the identification of patients with an optimal sensitivity and specificity, and a large part of variability among patients still remains unexplained. Furthermore, prospective clinical studies that should demonstrate the reliability of those pharmacokinetic and pharmacogenetic markers are still lacking. In the present review, pharmacokinetic and pharmacogenetic markers will be discussed.
The present results demonstrated significant differences in DPD and TP gene expression between normal mucosa and tumour samples, while TSER*3G/3G and high-grade histology were associated with significant variation in TS gene expression in tumour samples.
Daptomycin and linezolid, recently introduced to treat severe Gram-positive infections, are effective against multidrug-resistant Gram-positive microorganisms such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and vancomycin-resistant Enterococci bacteria that are less sensitive or frankly resistant, including methicillin-resistant S. aureus. However, alteration of their plasma profile has been described in some patients and this may be associated with toxicities or selection of resistant strains. The measurement of plasma concentrations of both drugs may allow the identification of those subjects at major risk of adverse events. Therefore, a rapid and sensitive high-performance liquid chromatography method for the analysis of daptomycin and linezolid was developed and applied in clinical settings. Drugs were extracted from plasma by adding methanol and, after centrifugation, clear supernatants were injected into the high-performance liquid chromatography system. Isocratic elution (1.5 mL/min) was performed using a mobile phase consisting of ammonium phosphate buffer 40 mM, pH 4.0, acetonitrile (70:30, vol/vol) through a BDS C8 Hypersil stationary phase (250 x 4.6 mm, 5 mum); ultraviolet detection was used at 214 nm. Linezolid and daptomycin eluted within 20 minutes from the injection, and mean recoveries ranged between 95.4% and 112.1%, respectively. The method was linear (coefficient of linearity, 0.998-0.999) over the full range of concentrations assayed, from 0.78125 mg/L (limit of quantitation) to 100 mg/L for both drugs. The Sy.x values were equal to 0.25 +/- 0.10 and 0.29 +/- 0.18 mg/L for daptomycin and linezolid, respectively. Precision values were lower than 20% over the entire range of calibration standard, and accuracy was within the range of 80% to 120% for all concentrations. The present method proved to be sensitive and specific to measure daptomycin and linezolid plasma concentrations in patients affected by severe Gram-positive infections, allowing therapeutic drug monitoring in those patients at major risk of severe adverse events.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.