The effect of food on the bioavailability of 6-mercaptopurine (6-MP) has been investigated. Seven patients were studied on two separate occasions. On the first occasion 6-MP was administered p.o. after an overnight fast and on the second, 15 min after a standard breakfast. 6-MP concentrations were determined by high-performance liquid chromatography. Variable plasma drug levels were observed between individual subjects in the fasting state. The peak levels of 6-MP were lower and took longer to be achieved following administration after a standard breakfast than after an overnight fast. In two subjects levels were undetectable (less than 20 ng/ml). In view of these observations it is suggested that 6-MP should be administered before food if maximum blood levels are to be achieved.
Optimised pre-clinical models are required for TB drug development to better predict the pharmacokinetics of anti-tuberculosis (anti-TB) drugs to shorten the time taken for novel drugs and combinations to be approved for clinical trial. Microdialysis can be used to measure unbound drug concentrations in awake freely moving animals in order to describe the pharmacokinetics of drugs in the organs as a continuous sampling technique. The aim of this work was to develop and optimise the microdialysis methodology in guinea pigs to better understand the pharmacokinetics of rifampicin in the lung. In vitro experiments were performed before progressing into in vivo studies because the recovery (concentration of the drug in the tissue fluid related to that in the collected dialysate) of rifampicin was dependent on a variety of experimental conditions. Mass spectrometry of the dialysate was used to determine the impact of flow rate, perfusion fluid and the molecular weight cut-off and membrane length of probes on the recovery of rifampicin at physiologically relevant concentrations. Following determination of probe efficiency and identification of a correlation between rifampicin concentrations in the lung and skeletal muscle, experiments were conducted to measure rifampicin in the sacrospinalis of guinea pigs using microdialysis. Lung concentrations of rifampicin were estimated from the rifampicin concentrations measured in the sacrospinalis. These studies suggest the potential usefulness of the microdialysis methodology to determine drug concentrations of selected anti-TB drugs to support new TB drug development.
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