Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC 50 values of losartan (42.7 µM), telmisartan (49.5 µM), irbesartan (55.6 µM), olmesartan (66.2 µM), candesartan (108 µM), and valsartan (279 µM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs.Key words epoxyeicosatrienoic acid; arachidonic acid; drug-endogenous interaction; angiotensin II receptor blocker; dihydroxyeicosatrienoic acid Arachidonic acid (AA), a component of the cell membrane, is known to be metabolized to prostaglandins, thromboxaneA 2 , leukotrienes and other bioactive substances 1) (Fig. 1). AA is also metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome P450 isoforms such as CYP 2C9, 2C8 and 2J2, and is further converted to the corresponding dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH).2-7) There are four structural isomers, 14,15-, 11,12-, 8,9-and 5,6-EET, that are reported to have vasodilatory and anti-inflammatory effects, while endothelium-derived hyperpolarizing factor (EDHF) action has been reported for 14,15-, 11,12-EET, [8][9][10][11][12] preconditioning effects have been reported for 14,15-EET, 13) and blood pressure regulating effects have been reported for 11,12-EET. 14)Totah and Rettie reported that CYP2C8, which constitutes about 7% of total microsomal CYP content in the human liver, appears to be important for metabolizing AA.15) CYP2C8 mainly generates 14,15-, 11,12-EET from AA, and the ratio of 14,15-EET : 11,12-EET is reported to be 1.25 : 1. 11) These results suggest that cardiovascular events such as hypertension and myocardial infarction are caused by decreased concentrations of these EETs.Angiotensin II receptor blockers (ARBs) are used for hypertensive patients with diabetes because of their cardio-and renoprotective effects. However, effects of ARBs other than the lowering of hypertension have recently been reported. 16)In a meta-a...
Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti-inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC ) of AA metabolism was losartan
Background: Recent reports highlight the importance of therapeutic drug monitoring (TDM) of BCR-ABL and Bruton tyrosine kinase inhibitors (TKIs); thus, large-scale studies are needed to determine the target concentrations of these drugs. TDM using dried plasma spots (DPS) instead of conventional plasma samples is a promising approach. This study aimed to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of BCR-ABL and Bruton TKIs for further TDM studies.Methods: A 20-mL aliquot of plasma was spotted onto a filter paper and dried completely. Analytes were extracted from 2 DPS using 250 mL of solvent. After cleanup by supported liquid extraction, the sample was analyzed by LC-MS/MS. Applicability of the method was examined using samples of patients' DPS transported by regular mail as a proof-of-concept study. The constant bias and proportional error between plasma and DPS concentrations were assessed by Passing-Bablok regression analysis, and systematic errors were evaluated by Bland-Altman analysis. Results:The method was successfully validated over the following calibration ranges: 1-200 ng/mL for dasatinib and ponatinib, 2-400 ng/mL for ibrutinib, 5-1000 ng/mL for bosutinib, and 20-4000 ng/ mL for imatinib and nilotinib. TKI concentrations were successfully determined for 93 of 96 DPS from clinical samples. No constant bias between plasma and DPS concentrations was observed for bosutinib, dasatinib, nilotinib, and ponatinib, whereas there were proportional errors between the plasma and DPS concentrations of nilotinib and ponatinib. Bland-Altman plots revealed that significant systematic errors existed between both methods for bosutinib, nilotinib, and ponatinib.Conclusions: An LC-MS/MS method for the simultaneous quantification of 6 TKIs in DPS was developed and validated. Further large-scale studies should be conducted to assess the consistency of concentration measurements obtained from plasma and DPS.
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