Inhibitory Effects of Angiotensin Receptor Blockers on CYP2C9 Activity in Human Liver Microsomes

Kamiyama, Emi; Yoshigae, Yasushi; Kasuya, Atsushi; Takei, Makoto; Kurihara, Atsushi; Ikeda, Toshihiko

doi:10.2133/dmpk.22.267

Cited by 27 publications

(26 citation statements)

References 18 publications

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“…Olmesartan, which has a lower affinity for CYP2C9, 25) showed intermediate inhibition of CYP2C8 in the present study. Candesartan has been reported to have weak effects on the inhibition of CYP2C8, and to have negligible accumulation with rapid elimination of radioactivity in plasma after administration of 14 C-labeled drugs.…”

Section: Discussionsupporting

confidence: 40%

Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8

Senda

Mukai

Toda

et al. 2015

Biological & Pharmaceutical Bulletin

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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...

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Section: Discussionsupporting

confidence: 40%

Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8

Senda

Mukai

Toda

et al. 2015

Biological & Pharmaceutical Bulletin

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“…20) Using this method, we demonstrated that several ARBs inhibit AA metabolism in recombinant CYP (rCYP) 2C8, 21) rCYP2C9, rCYP2J2, and HLMs 22) ; among the ARBs, telmisartan exhibited more potent inhibitory effect towards the CYP enzymes. 21,22) Several studies have revealed that telmisartan inhibits CYP2C9 23) and CYP2J2 24) in HLMs. Ren et al 24) reported that telmisartan is a mixed inhibitor of CYP2J2.…”

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confidence: 99%

The Inhibitory Effect of Telmisartan on the Metabolism of Arachidonic Acid by CYP2C9 and CYP2C8: An in Vitro Study

Kato

Mukai

Rane

et al. 2017

Biological & Pharmaceutical Bulletin

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Epoxyeicosatorienoic acids (EETs) are generated from arachidonic acid (AA) by CYPs. EETs comprise four regioisomers (14,15-, 11,12-, 8,9-, and 5,6-EET). EETs show potent physiological effects, including vasodilation, anti-inflammation, myocardial preconditioning, and anti-platelet aggregation effects. We recently demonstrated that telmisartan, one of angiotensin II receptor blockers, inhibits AA metabolism by CYP enzymes, including CYP2C8, CYP2C9, and CYP2J2. We conducted studies of AA metabolism using recombinant CYP enzymes to estimate the inhibition constant and the type of inhibition by telmisartan of CYP2C9 and CYP2C8. The contribution ratio (CR) of each CYP enzyme was investigated using human liver microsomes. Dixon and Lineweaver-Burk plots indicated that telmisartan is a mixed inhibitor of both CYP2C9 and CYP2C8; telmisartan did not show a time-dependent inhibition toward these CYP enzymes. Based on the CRs, both CYP2C9 and CYP2C8 are the key enzymes in the metabolism of AA in the human liver. Uptake of telmisartan in the liver by organic anion transporting polypeptide (OATP) 1B3 and the nonlinear metabolism in gastrointestinal tract augment the potential of the drug to inhibit the CYP enzymes in the liver.Key words epoxyeicosatrienoic acid; arachidonic acid; telmisartan; drug-endogenous interaction Arachidonic acid (AA) is a 20-carbon unsaturated fatty acid with double bonds at positions 14, 11, 8, and 5. AA is metabolized by cyclooxygenase and lipoxygenase as well as several CYPs including CYP2C8, CYP2C9, and CYP2J2.

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“…It is possible to assess the transport activity via these efflux transporters using Caco-2 cells cultured for 1 week as a first tier screening assay. However, it is difficult to correctly assess the transcellular transport activity of high hydrophilic compounds in Caco-2 cells cultured for 1 week, because the transcellular transport activity of olmesartan, a good substrate for hMRP2 (Nakagomi-Hagihara et al, 2006) and also a hydrophilic compound (Kamiyama et al, 2007), was observed only in the 2-week culture. Therefore, we suggest that it is better to perform a transport study as a first tier screening assay using Caco-2 cells cultured for 2 weeks rather than 1 week.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, four test compounds were selected: 1) digoxin, a typical hMDR1 substrate (Pedersen et al, 1983); 2) ochratoxin A, a specific substrate for hMRP2 that showed transcellular transport activity across Caco-2 cells (Berger et al, 2003); 3) olmesartan, a highly hydrophilic substrate for hMRP2 (Nakagomi-Hagihara et al, 2006;Kamiyama et al, 2007); and 4) estrone-3-sulfate (ES), a typical substrate of hBCRP (Xia et al, 2005).…”

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confidence: 99%

Culture Period-Dependent Change of Function and Expression of ATP-Binding Cassette Transporters in Caco-2 Cells

Kamiyama¹,

Sugiyama²,

Nakai³

et al. 2009

Drug Metab Dispos

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ABSTRACT:The objective of this study was to determine an appropriate culture period to assess whether a compound of interest is transported by efflux transporters such as human multidrug resistance 1 (hMDR1), human multidrug resistance-associated protein 2 (hMRP2), and human breast cancer resistance protein (hBCRP) in Caco-2 cells. Caco-2 cells were cultured on a Transwell for 1 to 6 weeks. The expression of these transporters in the mRNA and protein levels was examined using a real-time polymerase chain reaction and Western blotting, respectively. Transcellular transport activities using digoxin, ochratoxin A, olmesartan, and estrone-3-sulfate were also examined. Except for digoxin, the permeability coefficient (P app ) ratio of the three compounds at 2 weeks was the highest in the periods tested. The P app ratio of digoxin at 2 weeks was higher than that at 3 weeks. The temporal expression profile of each transporter in the mRNA level was similar to that in the protein level, and the functions of hMRP2 and hBCRP were roughly correlated with the expression in the mRNA and protein levels, but that of hMDR1 was not. These data suggest that among all the culture periods evaluated a 2-week culture is the best culture period for transport studies to identify whether a compound is a substrate for hMDR1, hMRP2, and hBCRP.

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Inhibitory Effects of Angiotensin Receptor Blockers on CYP2C9 Activity in Human Liver Microsomes

Cited by 27 publications

References 18 publications

Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid <i>via</i> CYP2C8

Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid <i>via</i> CYP2C8

The Inhibitory Effect of Telmisartan on the Metabolism of Arachidonic Acid by CYP2C9 and CYP2C8: An <i>in Vitro</i> Study

Culture Period-Dependent Change of Function and Expression of ATP-Binding Cassette Transporters in Caco-2 Cells

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