Paclitaxel alters the expression and specific activity of deoxycytidine kinase and cytidine deaminase in non-small cell lung cancer cell lines

<p>Abstract</p> <p>Background</p> <p>We observed that paclitaxel altered the pharmacokinetic properties of gemcitabine in patients with non-small cell lung cancer (NSCLC) and limited the accumulation of gemcitabine and its metabolites in various primary and immortalized human cells. Therefore, we classified the drug-drug interaction and the effects of paclitaxel on deoxycytidine kinase (dCK) and cytidine deaminase (CDA) in three NSCLC cell lines. These enzymes are responsible for the metabolism of gemcitabine to its deaminated metabolite dFdU (80% of the parent drug) and the phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP. These metabolites appear to relate to sensitivity and tolerability of gemcitabine based on previous animal and laboratory studies.</p> <p>Methods</p> <p>Three immortalized human cells representative of the most common histological subtypes identified in patients with advanced NSCLC were exposed to the individual drugs or combinations to complete a multiple drug effect analysis. These same cell lines were exposed to vehicle-control or paclitaxel and the mRNA levels, protein expression and specific activity of dCK and CDA were compared. Comparisons were made using a two-tailed paired t-test or analysis of variance with a P value of < 0.05 considered significant.</p> <p>Results</p> <p>The multiple drug effect analysis indicated synergy for H460, H520 and H838 cells independent of sequence. As anticipated, paclitaxel-gemcitabine increased the number of G2/M cells, whereas gemcitabine-paclitaxel increased the number of G0/G1 or S cells. Paclitaxel significantly decreased dCK and CDA mRNA levels in H460 and H520 cells (40% to 60%, P < 0.05) and lowered dCK protein (24% to 56%, P < 0.05) without affecting CDA protein. However, paclitaxel increased both dCK (10% to 50%) and CDA (75% to 153%) activity (P < 0.05). Paclitaxel caused substantial declines in the accumulation of the deaminated and phosphorylated metabolites in H520 cells (P < 0.05); the metabolites were not measurable in the remaining two cell lines. The ratio of dCK to CDA mRNA levels corresponded to the combination index (CI) estimated for sequential paclitaxel-gemcitabine.</p> <p>Conclusion</p> <p>In summary, paclitaxel altered the mRNA levels and specific activity of dCK and CDA and these effects could be dependent on histological subtype. More cell and animal studies are needed to further characterize the relationship between mRNA levels and the overall drug-drug interaction and the potential to use histological subtype as a predictive factor in the selection of an appropriate anticancer drug regimen.</p

EVALUATION OF THE CONTRIBUTION OF CYTOCHROME P450 3A4 TO HUMAN LIVER MICROSOMAL BUPROPION HYDROXYLATION

This paper is available online at http://dmd.aspetjournals.org ABSTRACT: The purpose of this investigation was to evaluate the role of cytochrome P450 (CYP) 3A4 in human liver microsomal bupropion (BUP) hydroxylation. Across the BUP concentration range of 0.075 to 12 mM, cDNA-expressed CYP3A4 demonstrated BUP hydroxylase activity only when incubated with concentrations &gt;4 mM. When assayed at 12 mM BUP, cDNA-expressed CYP3A4 catalyzed BUP hydroxylation at a 30-fold lower rate than cDNA-expressed CYP2B6 (0.2 versus 7 pmol/min/pmol of P450 Bupropion (BUP) 1 is a second-generation antidepressant agent that is also used in the management of smoking cessation. This drug undergoes extensive hepatic metabolism in humans via oxidative and reductive pathways Clinical pharmacokinetic studies have demonstrated 3-to 10-fold interindividual differences in HBUP C max and AUC In a prior in vitro study reported in abstract form, CYP3A4 demonstrated the second highest rate of BUP hydroxylation among a panel of cDNA-expressed P450 isozyme

Old and new oral anticoagulants : food, herbal medicines and drug interactions

The most commonly prescribed oral anticoagulants worldwide are the vitamin K antagonists (VKAs) such as warfarin. Factors affecting the pharmacokinetics of VKAs are important because deviations from their narrow therapeutic window can result in bleedings due to over-anticoagulation or thrombosis because of under-anticoagulation. In addition to pharmacodynamic interactions (e.g., augmented bleeding risk for concomitant use of NSAIDs), interactions with drugs, foods, herbs, and over-the-counter medications may affect the risk/benefit ratio of VKAs. Direct oral anticoagulants (DOACs) including Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and thrombin inhibitor (dabigatran) are poised to replace warfarin. Phase-3 studies and real-world evaluations have established that the safety profile of DOACs is superior to those of VKAs. However, some pharmacokinetic and pharmacodynamic interactions are expected. Herein we present a critical review of VKAs and DOACs with focus on their potential for interactions with drugs, foods, herbs and over-the-counter medications