Bioconcentration and Biotransformation of ... - ACS Publications

Subscriber access provided by University of Newcastle, Australia

Article

Bioconcentration and Biotransformation of Amitriptyline in Gilt-head Bream Haizea Ziarrusta, Leire Mijangos, Urtzi Izagirre, Merle M. Plassmann, Jonathan P. Benskin, Eneritz Anakabe, Maitane Olivares, and Olatz Zuloaga Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.6b05831 • Publication Date (Web): 20 Jan 2017 Downloaded from http://pubs.acs.org on January 22, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Environmental Science & Technology is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 27

Environmental Science & Technology

TOC/Abstract art TOC/Abstract art 67x47mm (300 x 300 DPI)

ACS Paragon Plus Environment


1

Bioconcentration and Biotransformation of Amitriptyline

2

in Gilt-head Bream

Page 2 of 27

3 4

Haizea Ziarrusta*,1,2 Leire Mijangos,1 Urtzi Izagirre,3 Merle M. Plassmann,2 Jonathan P.

5

Benskin,2 Eneritz Anakabe,4 Maitane Olivares,1 Olatz Zuloaga1,3

6 7

1. Department of Analytical Chemistry, University of the Basque Country (UPV/EHU), Leioa,

8

Basque Country, Spain

9

2. Department of Environmental Science and Analytical Chemistry (ACES), Stockholm

10

University, Stockholm, Sweden

11

3. Research Centre for Experimental Marine Biology and Biotechnology (PIE), University of the

12

Basque Country (UPV/ EHU), Plentzia, Basque Country, Spain

13

4. Department of Organic Chemistry, University of the Basque Country (UPV/EHU), Leioa,

14

Basque Country, Spain

15

16

17

18

19

*Corresponding author: Haizea Ziarrusta ([email protected])

20

Department of Analytical Chemistry, Faculty of Science and Technology, University of the

21

Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain.

22

Tel: + 34 94 601 55 51; Fax: +34 94 601 35 00

1 ACS Paragon Plus Environment

Page 3 of 27


23

ABSTRACT

24

Extensive global use of the serotonin-norepinephrine reuptake inhibitor Amitriptyline (AMI) for

25

treatment of depression has led to its ubiquitous occurrence in the aquatic environment. To

26

assess AMI bioconcentration factors, tissue distribution, and metabolite formation in fish, we

27

exposed gilt-head bream (Spaurus aurata) to AMI in seawater for 7 days at two concentrations

28

(0.2 µg/L and 10 µg/L). Day 7 proportional bioconcentration factors (BCFs) ranged from 6

29

(10 µg/L dose, muscle) to 127 (0.2 µg/L dose, brain) and were consistently larger at the low

30

dose level. The relative tissue distribution of AMI was consistent at both doses, with

31

concentrations decreasing in the order brain ≈ gill > liver > plasma > bile >> muscle. Using a

32

suspect screening workflow based on liquid chromatography–high resolution (Orbitrap) mass

33

spectrometry we identified 33 AMI metabolites (both Phase I and Phase II), occurring mostly in

34

bile, liver and plasma. Ten structures are reported for the first time. Remarkably, all 33

35

metabolites retained the tricyclic ring structure common to tricyclic antidepressants, which

36

may be toxicologically relevant. Collectively these data indicate that, in addition to AMI, a

37

broad suite of metabolites should be included in biomonitoring campaigns in order to fully

38

characterize exposure in aquatic wildlife.



Page 4 of 27

39

1. Introduction

40

Globally, amitriptyline (AMI) is among the most extensively prescribed pharmaceuticals for the

41

treatment of depression and psychiatric disorders (>10,000 kg in England alone for 2012).1 Like

42

other tricyclic antidepressants (TCAs), the mechanism of action of AMI involves inhibition of

43

norepinephrine and/or serotonin reuptake in the central nervous system, resulting in

44

increased neurotransmitter concentrations in the brain.2,3 AMI enters waste streams mainly

45

through human excretion.4 Despite considerable removal during wastewater treatment5 AMI is

46

detectable at concentrations of up to 72 ng/L in surface water and 223 ng/L in wastewater

47

treatment plant (WWTP) effluents.3,5-8

48

The disposition of AMI in mammalian models has been well studied as part of human

49

pharmaceutical safety assessments.9-11 However, few data exist for non-target organisms

50

which may be exposed unintentionally in the environment. In aquatic species, AMI may disrupt

51

the immune system and affect reproduction, development and growth at concentrations as

52

low as 10 ng/L.12-14 AMI also has the potential to bioaccumulate15 (log Kow = 4.81, pKa = 9.8 16),

53

and it has been observed in thicklip gray mullet (Chelon labrosus) liver from Spain8 and whole

54

mussels from San Francisco Bay17 at concentrations of 1.8 ng/g and 0.2 ng/g, respectively. A

55

systematic investigation of AMI uptake and tissue distribution in aquatic species has not yet

56

been conducted; however, a study involving brook trout (Salvelinus fontinalis) exposed to

57

3.7 ng/L of AMI via diluted WWTP effluents observed up to 0.29 ng/g in liver, and non-

58

detectable concentrations in muscle and brain.18 This result is surprising considering that

59

observations in other species indicate a tendency for AMI to partition to brain followed by

60

liver.9,10

61

Mammalian studies indicate that AMI is extensively biotransformed in the liver by cytochrome

62

P450 2D6 (CYP2D6) enzymes to a diverse range of potentially bioactive metabolites.2 In vitro

63

incubations involving human liver microsomes observed up to 50 possible AMI transformation 3 ACS Paragon Plus Environment

Page 5 of 27


64

products,19,20 while an additional 12 glucuronide conjugates were observed in human urine.20

65

Considerable inter-species variability in metabolism of AMI exists2,21,22 and to our knowledge

66

there are no data on biotransformation of AMI in aquatic organisms. Consequently,

67

environmental exposure assessments in aquatic wildlife which focus only on AMI, or a limited

68

number of mammalian metabolites, may underestimate the true extent of exposure.

69

The objective of the present work was to assess the distribution of AMI in fish in order to aid in

70

assessing the risk(s) associated with occurrence of this substance in the aquatic environment.

71

To achieve this goal, gilt-head bream (Spaurus aurata) were exposed to AMI in seawater for 7

72

days at two concentrations (0.2 µg/L and 10 µg/L). In addition to tissue-specific

73

bioconcentration factors, AMI-metabolites were characterized using a suspect screening

74

strategy involving high resolution mass spectrometry (HRMS). To our knowledge this is the first

75

time AMI uptake and biotransformation has been monitored in fish. These data provide

76

valuable information for assessing exposure of aquatic organisms to AMI and its potentially

77

bioactive metabolites.

78 79 80

2. Materials and methods 2.1. Standards and Reagents

81

Amitriptyline hydrochloride (AMI; 98 %), nortriptyline hydrochloride (NOR; 98 %), and the

82

isotopically-labelled internal standards 2H3-amitriptyline hydrochloride (2H3-AMI) and 2H3-

83

nortriptyline hydrochloride (2H3-NOR) were purchased from Sigma–Aldrich (St. Louis, MO,

84

USA). Stock dosing solutions of AMI were prepared at 5000 mg/L in methanol (MeOH) and

85

diluted down to 4.26 mg/L (high dose experiment) and 85.2 µg/L (low dose experiment) in

86

Milli-Q water. The final concentration of MeOH in the dosing solution was 0.98) between them taking into account the concentrations observed

214

at both dosing experiments, suggesting that AMI uptake occurred mainly through the gills and

215

not the gut.28 Similar results are reported in the literature for uptake of several

216

pharmaceuticals in wild fish exposed to wastewater.27 Though the uptake and tissue

217

distribution of ionisable compounds is generally pH-dependent,29-32 AMI is a weak base (pKa

218

9.8) with a relatively high hydrophobicity (log Kow of 4.81, log D 2.39 at pH 7.316), and

219

therefore, it is always positively charged at physiological pH.

220

With the exception of gill in the low-dose experiment, tissue BCFs were consistent over time

221

(p > 0.05), suggesting that steady state was reached after the 7-days of exposure at both

222

dosing levels (Figure 2). BCFs were higher in the low-dose experiment for brain, gill and liver,

223

suggesting a concentration dependency on the accumulation of AMI in fish. This result is

224

inconsistent with other studies investigating the effect of exposure concentration on

225

pharmaceutical uptake.33 Nevertheless, an inverse relationship between concentration and

226

BCF34 has been reported, possibly due to an increase in the reactive oxygen species (caused by

227

higher contaminant concentrations), which result in increased AMI biotransformation.35 The

228

same phenomena was not observed for muscle BCFs, but this could be due to the low

229

concentrations observed (close to limit of detection, and hence, wider variability) in this tissue.

230

There are few examples of tissue-specific BCFs determined for AMI in the peer-reviewed

231

literature.18 The limited existing data suggest that AMI BCFs are influenced by both inter-

232

species differences in uptake as well as exposure conditions. For example, a BCF=78 was

233

obtained for liver in book trout,18 which is in the same order of magnitude to the liver BCFs

234

calculated in the present work (21 at high dose, 48 at low dose). In contrast, much higher

235

values (BCF= 6028) were reported in mussels exposed to AMI via a river receiving wastewater

236

effluent.36 Additionally, it is germane to note that the BCFs in Figure 2 only take into account



Page 12 of 27

237

not metabolized AMI. Therefore, the BCFs may underestimate the total burden of

238

psychoactive drug in a given tissue, since they do not account for the presence of bioactive

239

metabolites, which could have an additive effect together with AMI.

240

3.2. Metabolite Identification

241

An overview of the biotransformation pathway with the annotated structures for AMI

242

metabolites in gilt-head bream is provided in Figure 3. Structural assignments based on

243

accurate mass and fragment ion data are summarized in Table S2. No reference standards

244

were available for the detected metabolites, thus we reached a confidence level 2b – 3

245

according to Schymanski et al.,37 leading to the assignments of probable structures or tentative

246

candidates. In all cases, the difference between measured and theoretical masses was

247

< 3.3 ppm. Nevertheless, due to the possibility of multiple isomers, structural assignments

248

were often ambiguous and relied on expert judgement. A total of 33 AMI transformation

249

products were observed, made up of both Phase I and Phase II metabolites. To the best of our

250

knowledge, 10 of these metabolites (M12, M13, M15, M16, M20, M21, M22, M23, M27 and

251

M28) are reported for the first time. Detailed information about the identification of individual

252

structures is compiled in the SI and summarized herein.

253

NOR (M1) was observed in all tissues and biofluids in the present work, but it was never the

254

major metabolite. This was surprising considering that N-demethylation of AMI to NOR (M1) is

255

the main metabolic route in human liver microsomes.19 Similarily, N, N- didemethylation 19,20

256

which was reported in human liver microsomes, was not observed in the present work. This

257

could be attributable to inter-species variability or to differences between in vivo and in vitro

258

biotransformation pathways. Despite these differences, oxidation remained a major metabolic

259

route of AMI in gilt-head bream, consistent with observations in humans.2 Up to 5 AMI

260

monohydroxylated metabolites of AMI and NOR (M2-M6) and an AMI N-oxidation metabolite

261

(M7) were observed (Figure 3). These structures are consistent with those observed from in


Page 13 of 27


262

vitro experiments involving AMI.19,20 Notably, M2 and M3 were estimated to be the most

263

abundant of all metabolites observed in the present work, based on a relative comparison of

264

peak areas.

265

M2/M3 (m/z 294.1857) and M4/M5 (m/z 280.1701) were identified as monohydroxylated

266

metabolites in the endocyclic ethylene group of AMI or NOR, respectively, according to the

267

observed fragmentation (see Figure S1a for M2/M3 and discussion in the SI). Hydroxylation in

268

the endocyclic ethylene group of the central ring of AMI is well described in the literature.2 On

269

the other hand, M6 (m/z 294.1857) was identified as a monohydroxylated metabolite of AMI

270

with the hydroxyl group in the exocyclic ethylene group of AMI (see Figure S1b) and M7 (m/z

271

294.1857) as a N-oxidation metabolite of AMI (commonly known as amitriptylinoxide) (see SI).

272

M8 (m/z 276.1752) likely forms from dehydration of M2/M3 according to the similar

273

fragmentation pattern observed (see SI). Similarly, M9 (m/z 262.1595) is likely formed from

274

dehydration of hydroxy-metabolites of NOR (i.e., M4/M5). Both M8 and M9 were identified

275

during in vitro experiments using human liver microsomes.20

276

M10 and M11 were identified as keto-derivatives of AMI in the central ring (m/z 292.1701)

277

(see discussion in SI), similar to the metabolites observed in in vitro experiments.19,20 M12 had

278

the same exact mass as M10/11 (m/z 292.1701) and was likely formed by dehydrogenation

279

plus methoxylation of NOR (see Figures S2a and S2b). M13 (m/z 306.1857) showed an

280

equivalent structure to M12 but with the tertiary amine head group as in AMI (see Figure S3c).

281

M14 (m/z 278.2544) corresponded to an epoxidation of M9 (see SI). Zhou and co-workers also

282

described epoxy metabolites as intermediate products20 and Liu et al. observed epoxy

283

metabolites during an investigation into the degradation of cyclobenzaprine.38

284

Five dioxidated metabolites of AMI (M15-M19; m/z 310.18066) and two of NOR (M20 and

285

M21; m/z 296.1650) were also identified in all the biological matrices except in muscle and



Page 14 of 27

286

brain. M15 and M16 metabolites showed a similar fragmentation pattern to one another, with

287

one hydroxylation on the endocyclic ethylene group and a N-oxydation. M17-M19 were

288

identified as dihydroxymetabolites in the endocyclic ethylene group of AMI (see Figure S3a),

289

which were also reported during in vitro experiments.20 M20 and M21 were identified as

290

dihydroxymetabolites of NOR in the endocyclic ethylene group (see Figure S3b). Compared to

291

Zhou and coworkers,20 we did not observe dihydroxy metabolites with one hydroxyl group in

292

the ethylene bridge and the other one in the aromatic ring. This may be due to interspecies

293

differences or due to in vitro20 versus in vivo test systems.

294

M22 (m/z 308.1650) showed a similar fragmentation pattern to M10/M11. This metabolite

295

contains a keto group in the endocyclic ethylene group and the second oxidation was

296

determined as a N-oxidation due to the lack of a second loss of water and the unmodified side

297

chain.

298

M23 (m/z 269.1541) could come from either AMI or NOR after the loss of (-C2H6N) or (-CH3N),

299

respectively, followed by dihydroxylation. However, due to poor fragmentation, we could not

300

locate these two hydroxyl groups in this metabolite.

301

Up to ten glucuronide derivatives were observed mainly in bile (M24-M33), of which seven

302

(M24-M26, M29, M30, M32 and M33) were previously reported by Zhou and co-workers in

303

human urine20. Although mentioned in the literature,2,19,20 N-glucuronidation of AMI was not

304

observed. This discrepancy may be attributed to the different glucuronidation process in

305

mammalian metabolism21 or due to metabolic differences arising from the use of in-vivo versus

306

in-vitro tests. In some cases we could determine the position of the glucuronide group but we

307

could not always determine where the conjugation (N- or O-glucuronidation) occurred, as is

308

also stated in the literature.39 M24-M26 (m/z 470.2178) was attributed to the glucuronidation

309

of M2/M3 based on the same fragment ions. This is consistent with Zhou et al.20 who also

310

found three glucuronide derivatives with the hydroxyl group at that position. M27 and M28 13 ACS Paragon Plus Environment

Page 15 of 27


311

(m/z 470.2178, see Figure S4 for fragmentation) were considered as N-glucuronides of

312

methoxy-metabolite of NOR in the endocyclic ethylene group. While monohydroxy-

313

metabolites of AMI in the aromatic ring were not observed in the present work, M29 (m/z

314

470.2178) was attributed to a glucuronide of a hydroxyl metabolite of AMI in an aromatic ring.

315

M30 (m/z 486.2127) was attributed to the glucuronidation of M17-M19. In the case of M31

316

(m/z 486.2127) we could not define the structure of this glucuronide metabolite. Finally,

317

glucuronides M32-M33 (m/z 456.2022) were only observed in bile and showed a similar

318

fragmentation in accordance with the fragmentation of M4-M5 monohydroxylates of NOR.

319

3.3. Changes in metabolite profiles with time and in different tissues

320

AMI metabolites were found primarily in bile (29), liver (21) and plasma (19) (see Table S2).

321

This is not surprising considering that liver is the main site of xenobiotic metabolism, and

322

metabolites formed in the liver are likely to undergo either systemic circulation (i.e. via

323

plasma) or elimination (via bile). Bile receives metabolites produced in both the liver and gut,

324

and thereby most metabolites were observed in bile.

325

Although it is only an approach, in order to compare the abundances of the different

326

metabolites in the different tissue/biofluids, we considered the same sensitivity for all the

327

metabolites. The relative abundances of metabolites (calculated as the ratio of the individual

328

peak area with respect to the sum of all peak areas) in different tissues and biofluids over the

329

course of the exposure period are shown in Figure 4. All peak areas were corrected using

330

sample size and internal standard (2H3-NOR). While metabolite profiles displayed considerable

331

differences between tissues/biofluids, the relative profile within a given tissue/biolfluid

332

remained fairly consistent over the duration of the experiment.

333

AMI was estimated to be the most abundant compound in comparison to its metabolites in gill

334

(30% of the total chromatographic peak area) and brain (40% of the total chromatographic

335

peak area). Gill is the area where contaminant uptake and elimination occurs, so high relative 14 ACS Paragon Plus Environment


Page 16 of 27

336

concentrations of AMI in this tissue are expected. In the case of brain the high abundance of

337

AMI is also expected due to passive diffusion across the blood-brain barrier is likely to favour

338

AMI as opposed to the more polar Phase I and II metabolites.10 Next to AMI, M2 (24 %) and

339

M13 (11 %) were the most abundant compounds detected in brain.

340

AMI in liver and plasma accounted for close to 20 % of the sum peak areas for all compounds,

341

highlighting the metabolic role of liver and the distribution role of plasma. M2 (30 %), was the

342

most abundant metabolite in liver whereas M10 (33 %), the dehydrogenation product of M2,

343

was mainly found in plasma. In contrast, AMI accounted for a very small (2%) proportion of the

344

sum peak areas in bile. Here, M24 and M26, glucuronide metabolites of M2/M3, were the

345

most abundant metabolites, accounting for approximately 30 % of the total peak area each.

346

3.4. Implications to Environmental Exposure Assessment

347

Assessing risks associated with the occurrence of pharmaceuticals in the aquatic environment

348

is hampered by the occurrence of numerous and potentially bioactive transformation

349

products. These substances may not be the same as those elucidated as part of initial

350

pharmaceutical safety assessments, on account of diverse reaction pathways occurring in the

351

environment but also inter-species differences in metabolism. In order to fully characterize the

352

extent of exposure to pharmaceuticals in aquatic wildlife, a complete understanding of the

353

numerous and potentially bioactive structures, and their tissue distribution, is required. In the

354

present work, brain contained the highest burden of AMI and only 10 metabolites, while liver

355

contained only ~20% of AMI and 21 metabolites. Consequently, standard exposure

356

assessments in aquatic wildlife focusing only on AMI in muscle or liver tissue would severely

357

underestimate the concentration of AMI in the target organ (brain) and completely overlook

358

the concentrations of potentially bioactive metabolites in the entire animal. In fact, recent

359

data suggest that hydroxylated and N-oxidated metabolites (including NOR) are active in

360

mammals, and may even be more bioactive than parent compounds.2,40-42 While this highlights


Page 17 of 27


361

the need to include transformation products in environmental exposure assessments, this

362

clearly represents a challenge, since authentic analytical standards are unavailable for many of

363

these substances. In the absence of analytical standards, a suspect screening analytical

364

approach, such as that employed here, can be an effective means of qualitative identification

365

of novel and potentially bioactive metabolites. Important structures identified through this

366

approach can then be confirmed and semi-quantified using an a posteriori approach at such

367

time that a standard becomes available.

368

4. Supporting Information

369

Reagents information; LC-QqQ-MS/MS and LC-q-Orbitrap analysis details; Table S1, Phase I and

370

Phase II reactions; Table S2, details for AMI and all annotated metabolites; Metabolite

371

identification decription; Figures S1-S4, MS2 spectra and fragmentation of some metabolites

372

(M2-M3, M6, M10-M11, M12, M13, M17-M18-M19, M20 and M27-M28).

373

5. Acknowledgements

374

This work was financially supported by the Ministry of Economy and Competitiveness through

375

the project CTM2014-56628-C3-1-R. H. Ziarrusta is grateful to the Spanish Ministry and L.

376

Mijangos to the Basque Government for their pre-doctoral fellowships.

377

6. References

378

(1)

Petrie, B.; Barden, R.; Kasprzyk-Hordern, B. A review on emerging contaminants in

379

wastewaters and the environment: Current knowledge, understudied areas and

380

recommendations for future monitoring. Water Res. 2015, 72, 3–27 DOI:

381

10.1016/j.watres.2014.08.053.

382

(2)

Breyer-Pfaff,

U.

The

Metabolic

Fate

of

Amitriptyline,

Nortriptyline

and

383

Amitriptylinoxide in Man. Drug Metab. Rev. 2004, 36 (3–4), 723–746 DOI:

384

10.1081/DMR-200033482.



385

(3)

Page 18 of 27

Lajeunesse, A.; Gagnon, C.; Sauvé, S. Determination of Basic Antidepressants and Their

386

N-Desmethyl Metabolites in Raw Sewage and Wastewater Using Solid-Phase

387

Extraction and Liquid Chromatography−Tandem Mass Spectrometry. Anal. Chem.

388

2008, 80 (14), 5325–5333 DOI: 10.1021/ac800162q.

389

(4)

Halling-Sørensen, B.; Nors Nielsen, S.; Lanzky, P. F.; Ingerslev, F.; Holten Lützhøft, H. C.;

390

Jørgensen, S. E. Occurrence, fate and effects of pharmaceutical substances in the

391

environment- A review. Chemosphere 1998, 36 (2), 357–393 DOI: 10.1016/S0045-

392

6535(97)00354-8.

393

(5)

Baker, D. R.; Kasprzyk-Hordern, B. Multi-residue analysis of drugs of abuse in

394

wastewater and surface water by solid-phase extraction and liquid chromatography–

395

positive electrospray ionisation tandem mass spectrometry. J. Chromatogr. A 2011,

396

1218 (12), 1620–1631 DOI: 10.1016/j.chroma.2011.01.060.

397

(6)

398 399

Calisto, V.; Esteves, V. I. Psychiatric pharmaceuticals in the environment. Chemosphere 2009, 77 (10), 1257–1274 DOI: 10.1016/j.chemosphere.2009.09.021.

(7)

Lajeunesse, A.; Smyth, S. A.; Barclay, K.; Sauvé, S.; Gagnon, C. Distribution of

400

antidepressant residues in wastewater and biosolids following different treatment

401

processes by municipal wastewater treatment plants in Canada. Water Res. 2012, 46

402

(17), 5600–5612 DOI: 10.1016/j.watres.2012.07.042.

403

(8)

Ziarrusta, H.; Mijangos, L.; Prieto, A.; Etxebarria, N.; Zuloaga, O.; Olivares, M.

404

Determination of tricyclic antidepressants in biota tissue and environmental waters by

405

liquid chromatography-tandem mass spectrometry. Anal. Bioanal. Chem. 2015, 408

406

(4), 1205–1216 DOI: 10.1007/s00216-015-9224-y.

407

(9)

Ohshima, N.; Kotaki, H.; Sawada, Y.; Iga, T. Tissue distribution and metabolism of

408

amitriptyline after repeated administration in rats. Drug Metab. Dispos. 1994, 22 (1),

409

21–25.


Page 19 of 27


410

(10)

Uhr, M.; Grauer, M. T.; Yassouridis, A.; Ebinger, M. Blood–brain barrier penetration

411

and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab)

412

knock-out mice and controls. J. Psychiatr. Res. 2007, 41 (1–2), 179–188 DOI:

413

10.1016/j.jpsychires.2005.10.005.

414

(11)

Saito, K.; Maekawa, K.; Ishikawa, M.; Senoo, Y.; Urata, M.; Murayama, M.; Nakatsu, N.;

415

Yamada, H.; Saito, Y. Glucosylceramide and Lysophosphatidylcholines as Potential

416

Blood Biomarkers for Drug-Induced Hepatic Phospholipidosis. Toxicol. Sci. 2014, 141

417

(2), 377–386 DOI: 10.1093/toxsci/kfu132.

418

(12)

Fong, P. P.; Ford, A. T. The biological effects of antidepressants on the molluscs and

419

crustaceans:

420

10.1016/j.aquatox.2013.12.003.

421

(13)

A

review.

Aquat.

Toxicol.

2014,

151,

4–13

DOI:

Minguez, L.; Farcy, E.; Ballandonne, C.; Lepailleur, A.; Serpentini, A.; Lebel, J.-M.;

422

Bureau, R.; Halm-Lemeille, M.-P. Acute toxicity of 8 antidepressants: What are their

423

modes

424

10.1016/j.chemosphere.2014.01.057.

425

(14)

of

action?

Chemosphere

2014,

108,

314–319

DOI:

Yang, M.; Qiu, W.; Chen, J.; Zhan, J.; Pan, C.; Lei, X.; Wu, M. Growth inhibition and

426

coordinated physiological regulation of zebrafish (Danio rerio) embryos upon sublethal

427

exposure to antidepressant amitriptyline. Aquat. Toxicol. 2014, 151, 68–76 DOI:

428

10.1016/j.aquatox.2013.12.029.

429

(15)

Zenker, A.; Cicero, M. R.; Prestinaci, F.; Bottoni, P.; Carere, M. Bioaccumulation and

430

biomagnification potential of pharmaceuticals with a focus to the aquatic

431

environment.

432

10.1016/j.jenvman.2013.12.017.

433 434

(16)

J.

Environ.

Manage.

2014,

133,

378–387

DOI:

Chemicalize - Instant Cheminformatics Solutions https://chemicalize.com/welcome (accessed Nov 10, 2016).



435

(17)

Page 20 of 27

Klosterhaus, S. L.; Grace, R.; Hamilton, M. C.; Yee, D. Method validation and

436

reconnaissance of pharmaceuticals, personal care products, and alkylphenols in

437

surface waters, sediments, and mussels in an urban estuary. Environ. Int. 2013, 54, 92–

438

99 DOI: 10.1016/j.envint.2013.01.009.

439

(18)

Lajeunesse, A.; Gagnon, C.; Gagné, F.; Louis, S.; Čejka, P.; Sauvé, S. Distribution of

440

antidepressants and their metabolites in brook trout exposed to municipal

441

wastewaters before and after ozone treatment – Evidence of biological effects.

442

Chemosphere 2011, 83 (4), 564–571 DOI: 10.1016/j.chemosphere.2010.12.026.

443

(19)

Rousu, T.; Herttuainen, J.; Tolonen, A. Comparison of triple quadrupole, hybrid linear

444

ion trap triple quadrupole, time-of-flight and LTQ-Orbitrap mass spectrometers in drug

445

discovery phase metabolite screening and identification in vitro – amitriptyline and

446

verapamil as model compounds. Rapid Commun. Mass Spectrom. 2010, 24 (7), 939–

447

957 DOI: 10.1002/rcm.4465.

448

(20)

Zhou, X.; Chen, C.; Zhang, F.; Zhang, Y.; Feng, Y.; Ouyang, H.; Xu, Y.; Jiang, H.

449

Metabolism and bioactivation of the tricyclic antidepressant amitriptyline in human

450

liver microsomes and human urine. Bioanalysis 2016, 8 (13), 1365–1381 DOI:

451

10.4155/bio-2016-0025.

452

(21)

Chiu, S.-H. L.; Huskey, S.-E. W. Species Differences in N-Glucuronidation 1996 ASPET N-

453

Glucuronidation of Xenobiotics Symposium. Drug Metab. Dispos. 1998, 26 (9), 838–

454

847.

455

(22)

Pelkonen, O. Comparison of metabolic stability and metabolite identification of 55

456

ECVAM/ICCVAM validation compounds between human and rat liver homogenates

457

and

458

issue.50.html?iid=107&aid=5 (accessed Jul 22, 2016).

459 460

(23)

microsomes

-

a

preliminary

analysis

http://www.altex.ch/Current-

Nallani, G. C.; Paulos, P. M.; Constantine, L. A.; Venables, B. J.; Huggett, D. B. Bioconcentration of ibuprofen in fathead minnow (Pimephales promelas) and channel 19 ACS Paragon Plus Environment

Page 21 of 27


461

catfish (Ictalurus punctatus). Chemosphere 2011, 84 (10), 1371–1377 DOI:

462

10.1016/j.chemosphere.2011.05.008.

463

(24)

Brooks, B. W.; Chambliss, C. K.; Stanley, J. K.; Ramirez, A.; Banks, K. E.; Johnson, R. D.;

464

Lewis, R. J. Determination of select antidepressants in fish from an effluent-dominated

465

stream. Environ. Toxicol. Chem. 2005, 24 (2), 464–469 DOI: 10.1897/04-081R.1.

466

(25)

Nallani, G. C.; Edziyie, R. E.; Paulos, P. M.; Venables, B. J.; Constantine, L. A.; Huggett,

467

D. B. Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish.

468

Environ. Toxicol. Chem. 2016, 35 (3), 593–603 DOI: 10.1002/etc.3244.

469

(26)

Schultz, M. M.; Painter, M. M.; Bartell, S. E.; Logue, A.; Furlong, E. T.; Werner, S. L.;

470

Schoenfuss, H. L. Selective uptake and biological consequences of environmentally

471

relevant antidepressant pharmaceutical exposures on male fathead minnows. Aquat.

472

Toxicol. 2011, 104 (1–2), 38–47 DOI: 10.1016/j.aquatox.2011.03.011.

473

(27)

Tanoue, R.; Nomiyama, K.; Nakamura, H.; Kim, J.-W.; Isobe, T.; Shinohara, R.; Kunisue,

474

T.; Tanabe, S. Uptake and Tissue Distribution of Pharmaceuticals and Personal Care

475

Products in Wild Fish from Treated-Wastewater-Impacted Streams. Environ. Sci.

476

Technol. 2015, 49 (19), 11649–11658 DOI: 10.1021/acs.est.5b02478.

477

(28)

Qiao, P.; Gobas, F. A.; Farrell, A. P. Relative contributions of aqueous and dietary

478

uptake of hydrophobic chemicals to the body burden in juvenile rainbow trout. Arch.

479

Environ. Contam. Toxicol. 2000, 39 (3), 369–377.

480

(29)

Meredith-Williams, M.; Carter, L. J.; Fussell, R.; Raffaelli, D.; Ashauer, R.; Boxall, A. B. A.

481

Uptake and depuration of pharmaceuticals in aquatic invertebrates. Environ. Pollut.

482

2012, 165, 250–258 DOI: 10.1016/j.envpol.2011.11.029.

483

(30)

Nakamura, Y.; Yamamoto, H.; Sekizawa, J.; Kondo, T.; Hirai, N.; Tatarazako, N. The

484

effects of pH on fluoxetine in Japanese medaka (Oryzias latipes): Acute toxicity in fish

485

larvae and bioaccumulation in juvenile fish. Chemosphere 2008, 70 (5), 865–873 DOI:

486

10.1016/j.chemosphere.2007.06.089. 20 ACS Paragon Plus Environment


487

(31)

Page 22 of 27

Erickson, R. J.; McKim, J. M.; Lien, G. J.; Hoffman, A. D.; Batterman, S. L. Uptake and

488

elimination of ionizable organic chemicals at fish gills: I. Model formulation,

489

parameterization, and behavior. Environ. Toxicol. Chem. 2006, 25 (6), 1512–1521 DOI:

490

10.1897/05-358R.1.

491

(32)

Zhao, J.-L.; Liu, Y.-S.; Liu, W.-R.; Jiang, Y.-X.; Su, H.-C.; Zhang, Q.-Q.; Chen, X.-W.; Yang,

492

Y.-Y.; Chen, J.; Liu, S.-S.; et al. Tissue-specific bioaccumulation of human and veterinary

493

antibiotics in bile, plasma, liver and muscle tissues of wild fish from a highly urbanized

494

region. Environ. Pollut. 2015, 198, 15–24 DOI: 10.1016/j.envpol.2014.12.026.

495

(33)

Steele IV, W. B.; Garcia, S. N.; Huggett, D. B.; Venables, B. J.; Barnes III, S. E.; La Point, T.

496

W.

497

medroxyprogesterone acetate in the common carp (Cyprinus carpio). Environ. Toxicol.

498

Pharmacol. 2013, 36 (3), 1120–1126 DOI: 10.1016/j.etap.2013.09.013.

499

(34)

Tissue-specific

bioconcentration

of

the

synthetic

steroid

hormone

Wu, M.; Pan, C.; Yang, M.; Xu, B.; Lei, X.; Ma, J.; Cai, L.; Chen, J. Chemical analysis of

500

fish bile extracts for monitoring endocrine disrupting chemical exposure in water:

501

Bisphenol A, alkylphenols, and norethindrone. Environ. Toxicol. Chem. 2016, 35 (1),

502

182–190 DOI: 10.1002/etc.3176.

503

(35)

Xu, H.; Yang, M.; Qiu, W.; Pan, C.; Wu, M. The impact of endocrine-disrupting

504

chemicals on oxidative stress and innate immune response in zebrafish embryos.

505

Environ. Toxicol. Chem. 2013, 32 (8), 1793–1799 DOI: 10.1002/etc.2245.

506

(36)

de Solla, S. R.; Gilroy, È. A. M.; Klinck, J. S.; King, L. E.; McInnis, R.; Struger, J.; Backus, S.

507

M.; Gillis, P. L. Bioaccumulation of pharmaceuticals and personal care products in the

508

unionid mussel Lasmigona costata in a river receiving wastewater effluent.

509

Chemosphere 2016, 146, 486–496 DOI: 10.1016/j.chemosphere.2015.12.022.

510

(37)

Schymanski, E. L.; Jeon, J.; Gulde, R.; Fenner, K.; Ruff, M.; Singer, H. P.; Hollender, J.

511

Identifying Small Molecules via High Resolution Mass Spectrometry: Communicating

512

Confidence. Environ. Sci. Technol. 2014, 48 (4), 2097–2098 DOI: 10.1021/es5002105. 21 ACS Paragon Plus Environment

Page 23 of 27


513

(38)

514 515

Liu, Y.; Zhao, D.; Zhao, Z. (Zack). Study of degradation mechanisms of cyclobenzaprine by LC-MS/MS. Anal. Methods 2014, 6 (7), 2320 DOI: 10.1039/c3ay41409d.

(39)

Holčapek, M.; Kolářová, L.; Nobilis, M. High-performance liquid chromatography–

516

tandem mass spectrometry in the identification and determination of phase I and

517

phase II drug metabolites. Anal. Bioanal. Chem. 2008, 391 (1), 59–78 DOI:

518

10.1007/s00216-008-1962-7.

519

(40)

520 521

Gillman, P. K. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br. J. Pharmacol. 2007, 151 (6), 737–748 DOI: 10.1038/sj.bjp.0707253.

(41)

Nałęcz-Jawecki, G. In Vitro Biotransformation of Amitriptyline and Imipramine with Rat

522

Hepatic S9 Fraction: Evaluation of the Toxicity with Spirotox and Thamnotoxkit FTM

523

Tests. Arch. Environ. Contam. Toxicol. 2007, 54 (2), 266–273 DOI: 10.1007/s00244-007-

524

9052-y.

525

(42)

Hicks, J. K.; Swen, J. J.; Thorn, C. F.; Sangkuhl, K.; Kharasch, E. D.; Ellingrod, V. L.; Skaar,

526

T. C.; Müller, D. J.; Gaedigk, A.; Stingl, J. C. Clinical Pharmacogenetics Implementation

527

Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic

528

Antidepressants.

529

10.1038/clpt.2013.2.

Clin.

Pharmacol.

Ther.

2013,

93

(5),

402–408

DOI:

530



Figure 1. Concentration of AMI in the different tissues (as ng/g) and fluids (as ng/mL) plus the confidence intervals (as two times the standard deviation, n=3, for a 95 % of confidence level) detected for fishes exposed to 10 µg/L (a) and 0.2 µg/L (b) of AMI. Concentrations of NOR (c) in fish exposed to 10 µg/L of AMI. Figure 1 179x300mm (96 x 96 DPI)


Page 24 of 27

Page 25 of 27


Figure 2: Evolution of BCF values and confidence interval (expressed as two times the standard deviation, n=3, 95 % of confidence level) in the different tissues: (a) brain, (b) gill, (c) liver and (b) muscle during the uptake. Note: even if the steady-state was not reached in some cases, BCFs were calculated as the ratio between AMI concentration in each fish tissue and the average water concentration during the uptake. Asterisk indicates significant differences (p < 0.05) between the values in high and low dosing levels. Figure 2 300x179mm (96 x 96 DPI)



Figure 3: Biotransformation pathway of AMI in Gilt-head bream. Inset shows MS/MS fragmentation and major m/z ions. The circles indicate that bond can take place at any position. Figure 3 349x203mm (300 x 300 DPI)


Page 26 of 27

Page 27 of 27


Figure 4. Relative abundances of AMI and its metabolites (calculated as the proportion of the sum peak areas) in biological tissues (muscle, brain, gill and liver) and fluids (plasma and bile) along the AMI exposure experiment (day 2, 4 and 7). Figure 4 300x179mm (96 x 96 DPI)


Bioconcentration and Biotransformation of ... - ACS Publications

Recommend Documents