Treatment Strategy for Cancer-associated Venous Thromboembolism During Chemotherapy: The Keep ACT2 Concept

Background/Aim: The frequency of detecting cancer-associated venous thromboembolism (CAT) during chemotherapy is increasing. It is not desirable to discontinue chemotherapy for CAT. In this study, we investigated the feasibility of simultaneous progression of anticoagulant and anticancer therapy, focusing on drug interactions. Patients and Methods: We retrospectively evaluated patients with gastroenterological CAT from February 2017 to December 2020 at the Gifu University Hospital. When both chemotherapy and CAT treatments using edoxaban were performed in parallel and the thrombus disappeared, patients were defined as being Keep-ACT2 (keeping anticancer therapy and anticoagulant therapy) successful. The effect and safety of treatment strategy focusing on cytochrome P450 (CYP) metabolism using edoxaban were evaluated. Results: A total of 114 patients with CAT during chemotherapy were treated with edoxaban. Keep-ACT2 was successful in 101 (88.6%) cases. Clinically relevant non-major bleeding was observed in 5 cases (4.4%). All 114 patients were using some drug affected by CYP metabolism, and the median number of affected cases was 5. Conclusion: Combined use of edoxaban for CAT may lead to sustainable therapy for gastroenterological cancer patients who are administered several drugs.

Expression of Cytochrome P450 Enzymes Is Induced by Flaxseed Enterolignans

Objectives The major flaxseed lignan, secoisolariciresinol diglucoside (SDG), is metabolized to bioactive enterolignans in the intestine and liver. Once formed, enterolignans are subject to hepatic conjugation, similar to cytochrome P450 (CYP)-mediated conjugation of many drugs. CYPs also metabolize food-derived phytochemicals; therefore, adding flaxseed to the diet may promote drug-nutrient interactions affecting the potency of medications. Clinical trials have shown blood pressure-lowering effects of flaxseed in hypertensive patients; however, it is unknown if this stems from direct actions of flaxseed bioactives or indirectly from increased circulating levels of anti-hypertensive (AH) medications resulting from competition for CYP-mediated conjugation and inactivation. Our objective was to determine if enterolignans produced from flaxseed SDG affect expression or activity of CYP enzymes that metabolize metoprolol (MET), a commonly-prescribed AH medication. Methods 3D human hepatocyte spheroids were treated with 25 μM MET or 1, 10, or 100 μM enterodiol (END) for 48 hours, after which RNA was extracted for qPCR analysis of expression of CYP2C9 and CYP3A4, two CYP isozymes involved in MET metabolism. Spheroids were also treated with the same concentrations of MET and END for 1 and 48 hours to measure MET and END metabolites using HPLC/LC-QTOF-MS analysis. Differences were tested with 1-way ANOVA with Tukey's post-hoc test. Results MET, 1 μM END, and 10 μM END all induced an approximate 2-fold increase in CYP2C9 expression, while 100 μM END induced a 4-fold increase (P < 0.05). CYP3A4 expression was induced 5-fold by MET, while 1 μM and 10 μM END produced only a 2-fold increase in CYP3A4 expression (P < 0.05). 100 μM END led to an almost 14-fold increase in CYP3A4 expression (P < 0.05). Compared to 1 hour of co-treatment with 25 μM MET + END, O-demethylmetoprolol in media was significantly lower after 48 hours (P < 0.05), suggesting competition between END and MET for CYP metabolism. Conclusions Our initial experiments in 3D human hepatic spheroids are the first to show that metabolites of flaxseed lignans induce expression of CYP2C9 and CYP3A4. The fact that flaxseed enterolignans induce the same CYPs as MET supports the hypothesis of shared metabolism and potential metabolic competition between enterolignans and AH medications. Funding Sources NSERC Discovery Grant.

MO323MEDICATION INDUCED RELAPSE OF FGSG

Background and Aims 31-year-old female with past medical history of Multiple Sclerosis diagnosed with Minimal Change Disease (MCD) in 2011. At diagnosis she had proteinuria that exceeded 7 g per day. She was treated with steroids and went into complete remission. In 2017 presented again with nephrotic syndrome and on repeat biopsy she was diagnosed with Focal Segmental Glomerulosclerosis (FSGS). She was restarted on steroids and had some improvement but despite 20 weeks of high dose steroids did not achieve remission. After every attempt of tapering, she would relapse. Method Other treatments tried without success were tacrolimus, cyclophosphamide and rituximab. Mild improvement with tacrolimus but stopped after a grand mal seizure. The lowest achievable steroid dose was 20mg daily. She was started on combination therapy tacrolimus and mycophenolate mofetil and was able to come off steroids and went into remission. Results After a few months of remission, she began to relapse. It was noted after extensive investigation that she had been placed on cabergolin for hyperprolactinemia by her endocrinologist at the time she began to relapse. Cabergolin was stopped and she went into remission again. We present the first case of FSGS relapse due to cabergolin. Conclusion Cabergoline is metabolized by hydrolysis and has limited cytochrome P450 (CYP) metabolism. Despite limited CYP metabolism, cabergoline does have an interaction with clarithromycin, a known inhibitor of CYP and p-glycoprotein. One rat study suggest that mycophenolate is a substrate for p-glycoprotein, so it is possible that there is some competitive inhibition. This would explain why the patient relapsed while on cabergoline and in remission after stopping it.

Drug-Drug Interactions of P-gp Substrates Unrelated to CYP Metabolism

Background: Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by ≧1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-gp are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs. Objective: Since there are no detailed manuscripts that summarizes P-gp interactions unrelated to CYP metabolism, this article reviews the effects of potent P-gp inhibitors and P-gp inducers on the pharmacokinetics of P-gp substrate drugs, including digoxin, talinolol, dabigatran etexilate, and fexofenadine in human studies. In addition, the present outcome were to determine the PK changes caused by DDIs among P-gp substrate drugs without CYP metabolism in human DDI studies. Conclusion: Our manuscript concludes that the PK changes of the DDIs among P-gp drugs unrelated to CYP metabolism are less likely to be serious, and it appears to be convincing that the absences of clinical effects caused to the PK changes by the P-gp inducers is predominant compared with the excessive effects caused to those by the P-gp inhibitors.

Improvement of the chemical inhibition phenotyping assay by cross-reactivity correction

Background:The fraction of an absorbed drug metabolized by the different hepatic cytochrome P450 (CYP) enzymes, relative to total hepatic CYP metabolism (Methods:To overcome this drawback, the cross-reactivities exhibited by six chemical inhibitors (furafylline, montelukast, sulfaphenazole, ticlopidine, quinidine and ketoconazole) were quantified using specific CYP enzyme marker reactions. The determined cross-reactivities were used to correct theResults:UncorrectedConclusions:Correcting