<b>Investigation of diltiazem metabolism in fish using a hybrid quadrupole/orbital trap mass spectrometer</b>

Koba, Olga; Steinbach, Christoph; Kroupová, Hana Kocour; Grabicová, Kateřina; Randák, Tomáš; Grabic, Roman

doi:10.1002/rcm.7543

Cited by 3 publications

(3 citation statements)

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“…The calculated half‐life for diltiazem across whole‐body tissues analyzed ranged from 1.5 (liver) to 49 h (muscle). In the same and follow‐up studies, 17 phase I diltiazem metabolites were detected in rainbow trout (Koba et al ; Steinbach et al 2016b). In humans, diltiazem has 3 main metabolites that are produced by phase I cytochrome P450 enzymes (CYP) 3A4 and 2D6 among others (Law et al ; Wishart et al ).…”

Section: Discussionmentioning

confidence: 85%

“…This class of chemicals has been commonly detected in surface water for almost 2 decades at low ng/L concentrations in developed countries; nevertheless, global hazards of CCBs in environmental matrices are understudied in major geographic regions (Saari et al ). Diltiazem has been detected in osprey plasma at low µg/L levels (0.5–8.6 µg/L) in the US mid‐Atlantic region (Bean et al ; Lazarus et al ), and several diltiazem metabolites have been reported in water and fish tissue (Koba et al ; Saari et al ; Steinbach et al ). Diltiazem is metabolized by liver cytochrome P450 3A4 and others in mammals, although no in vitro biotransformation was reported in rainbow trout S9 fractions (Connors et al ; Law et al ).…”

Section: Introductionmentioning

confidence: 99%

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Influence of Diltiazem on Fathead Minnows Across Dissolved Oxygen Gradients

Saari

Corrales

Haddad

et al. 2018

Enviro Toxic and Chemistry

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Water resources in many arid to semi-arid regions are stressed by population growth and drought. Growing populations and climatic changes are influencing contaminant and water chemistry dynamics in urban inland waters, where flows can be dominated by, or even dependent on, wastewater effluent discharge. In these watersheds, interacting stressors such as dissolved oxygen and environmental contaminants (e.g., pharmaceuticals) have the potential to affect fish physiology and populations. Recent field observations from our group identified the calcium channel blocker (CCB) diltiazem in fish plasma exceeding human therapeutic doses (e.g., C ) in aquatic systems impaired because of nonattainment of dissolved oxygen water quality standards. Therefore our study objectives examined: 1) standard acute and chronic effects of dissolved oxygen and diltiazem to fish, 2) influences of dissolved oxygen at criteria levels deemed protective of aquatic life on diltiazem toxicity to fish, and 3) whether sublethal effects occur at diltiazem water concentrations predicted to cause a human therapeutic level (therapeutic hazard value [THV]) in fish plasma. Dissolved oxygen × diltiazem co-exposures significantly decreased survival at typical stream, lake, and reservoir water quality standards of 5.0 and 3.0 mg dissolved oxygen/L. Dissolved oxygen and diltiazem growth effects were observed at 2 times and 10 times lower than median lethal concentration (LC50) values (1.7 and 28.2 mg/L, respectively). Larval fathead minnow (Pimephales promelas) swimming behavior following low dissolved oxygen and diltiazem exposure generally decreased and was significantly reduced in light-to-dark bursting distance traveled, number of movements, and duration at concentrations as low as the THV. Individual and population level consequences of such responses are not yet understood, particularly in older organisms or other species; however, these findings suggest that assessments with pharmaceuticals and other cardioactive contaminants may underestimate adverse outcomes in fish across dissolved oxygen levels considered protective of aquatic life. Environ Toxicol Chem 2018;37:2835-2850. © 2018 SETAC.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Influence of Diltiazem on Fathead Minnows Across Dissolved Oxygen Gradients

Saari

Corrales

Haddad

et al. 2018

Enviro Toxic and Chemistry

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“…Fish is a good indicator of the presence of pharmaceuticals in water, based on their low capacity to metabolize and then eliminate them [16]. However, under well-controlled experimental conditions, when fish are kept in water tanks, and pure pharmaceuticals (e.g., diltiazem) are applied to water for research purposes, the presence of metabolites after a certain time was also detected in water [17,18]. Therefore, in in situ tests in cascade ponds in Vodňany town, citalopram, metoprolol, sertraline, venlafaxine, and their metabolites have been detected in common carp fish hepatic tissue, water, and soil [19,20].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Metabolic Transformation of Pharmaceuticals by Hepatic S9 Fractions from Common Carp (Cyprinus carpio)

et al. 2020

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Water from wastewater treatment plants contains concentrations of pharmaceutically active compounds as high as micrograms per liter, which can adversely affect fish health and behavior, and contaminate the food chain. Here, we tested the ability of the common carp hepatic S9 fraction to produce the main metabolites from citalopram, metoprolol, sertraline, and venlafaxine. Metabolism in fish S9 fractions was compared to that in sheep. The metabolism of citalopram was further studied in fish. Our results suggest a large difference in the rate of metabolites formation between fish and sheep. Fish hepatic S9 fractions do not show an ability to form metabolites from venlafaxine, which was also the case for sheep. Citalopram, metoprolol, and sertraline were metabolized by both fish and sheep S9. Citalopram showed concentration-dependent N-desmethylcitalopram formation with Vmax = 1781 pmol/min/mg and Km = 29.7 μM. The presence of ellipticine, a specific CYP1A inhibitor, in the incubations reduced the formation of N-desmethylcitalopram by 30–100% depending on the applied concentration. These findings suggest that CYP1A is the major enzyme contributing to the formation of N-desmethylcitalopram. In summary, the results from the present in vitro study suggest that common carp can form the major metabolites of citalopram, metoprolol, and sertraline.

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