PubMed · 11503321
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H M Markusse. 2001-07-28. [Diagnostic image (32)].. https://pubmed.ncbi.nlm.nih.gov/11503321/
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A simple, rapid method of determining the ibuprofen concentration in small volumes of human plasma (50 microl) by HPLC was developed. The sample was prepared for injection using a solid-phase extraction method, with naproxen as the internal standard. A 96-well extraction plate was used, easing sample preparation and allowing the simultaneous extraction of multiple plasma samples directly into the HPLC injection vials. Samples were stable at room temperature for at least 48 h prior to injection. The HPLC method used an ultraviolet detector with a 5-min run time and measured concentrations across the range typically seen with the clinical use of this drug. The calibration curve was linear across the concentration range of 0.78-100 microg/ml with a limit of quantitation (LOQ) of 1.56 microg/ml. The coefficient of variation for intra-day and inter-day precision was 6% or less with accuracies within 2% of the nominal values for low (4.5 microg/ml), medium (40 microg/ml) and high (85 microg/ml) ibuprofen concentrations. For ibuprofen concentrations at the LOQ, the intra-day and inter-day precision and accuracy were within 10 and 15%, respectively. Recovery was 87% or greater for ibuprofen. This method was used to analyze plasma samples for unknown ibuprofen concentrations in bioequivalence and limited food effect studies of different formulations of ibuprofen. Thus, this method has been fully validated and used in the analysis of unknown plasma samples for ibuprofen.
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The cyclooxygenase-2 (COX-2) gene encodes an inducible enzyme that converts arachidonic acid to prostaglandins and is up-regulated in colorectal neoplasms. Evidence indicates that COX-2 may regulate apoptosis and can influence the malignant phenotype. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzymes and induce apoptosis in colorectal cancer cell lines, which may contribute to their antitumor effects. To determine whether forced COX-2 expression modulates susceptibility to drug-induced apoptosis, HCT-15 colon carcinoma cells were stably transfected with the COX-2 cDNA, and two clones overexpressing COX-2 were isolated. Selective COX-2 (NS398) and nonselective (sulindac sulfide) COX inhibitors, as well as 5-fluorouracil (5-FU), induced apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling in a dosage-dependent manner. Forced COX-2 expression significantly attenuated induction of apoptosis by all three of the drugs compared with parental HCT-15 cells. NSAIDs and 5-FU induced the mitochondrial release of cytochrome c as well as caspase-3 and -9 activation, and to a much lesser extent, caspase-8. COX-2-overexpressing cells showed reduced cytochrome c and caspase activation, relative to parental cells. A specific inhibitor of caspase-3 restored cell survival after drug treatment. COX-2 transfectants were found to overexpress the antiapoptotic Bcl-2 mRNA and protein relative to parental cells. In conclusion, forced COX-2 expression significantly attenuates apoptosis induction by NSAIDs and 5-FU through predominant inhibition of the cytochrome c-dependent apoptotic pathway. COX-2-mediated up-regulation of Bcl-2 suggests a potential mechanism for reduced apoptotic susceptibility.