Determination of sildenafil and tadalafil adulteration by LC-MS/MS and 23 elements by ICP-MS in food supplements

Year 2023, Volume: 53 Issue: 2, 219 - 228, 30.08.2023

Çağatay Oltulu , Saffet Çelik , Mustafa Daşman

https://doi.org/10.26650/IstanbulJPharm.2023.1206425

Abstract

Background and Aims: Since the increasing prevalence of erectile dysfunction disease, the use of phosphodiesterase type 5 (PDE-5) inhibitors is widespread in the current era. The first and the most known molecule of PDE-5 inhibitors is sildenafil. It is widely used in the market. The second and more developed one is tadalafil. It is known that these substances are found in sexual stimulant food supplements as adulteration. In addition, food supplements can contain metals that can cause hazardous activity by accumulating. In our study, 11 randomly chosen sexual stimulant known products are studied which were bought from different stores in Edirne.
Methods: Adulteration with sildenafil and tadalafil was determined by LC-MS/MS because of the enhanced accuracy and precision, general applicability, and higher selectivity. Also, the determination of 23 metals, including known heavy metals, was made with ICP-MS.
Results: In the study, 7 of 11 samples detected at least 1 compound of sildenafil (up to 92.44 mg in one serving) or tadalafil (up to 23.62 mg in one serving). Neither of the samples exceeded the limits of metal daily intakes that are shown in Table 4.
Conclusion: In past studies, adulteration was determined in food supplements, and it is still detected today. The results we obtained are engrossing for the regulations of sexual stimulant food supplement sales. Their additional effects on total daily intake raise health concerns. The data obtained from this study will contribute to inform consumers and health professionals about the status of food supplements in the market.

Keywords

Adulteration, dietary food supplements, metals, PDE-5 inhibitors, sildenafil, tadalafil

References

• Ahmad, N., Akhtar, M. S., Ahmed, R., Zafar, R., Hussain, S., Ishaqe, M., Naeem, M. (2019). Assessment of heavy metals in vegetables, sewage and soil grown near Babu Sabu Toll Plaza of Lahore, Pakistan. Pakistan Journal of Analytical & Environmental Chemistry, 20(1), 82-87. http://dx.doi.org/10.21743/pjaec/2019.06.11 google scholar
• Akinyele, I. O., & Shokunbi, O. S. (2015). Concentrations of Mn, Fe, Cu, Zn, Cr, Cd, Pb, Ni in selected Nigerian tubers, legumes and ce-reals and estimates of the adult daily intakes. Food Chemistry, 173, 702-708. https://doi.org/10.1016/j.foodchem.2014.10.098 google scholar
• Altundağ, H., Yildirim, E., & Altıntığ, E. (2019). Determination of some heavy metals by ICP-OES in edible parts of fish from Sapanca Lake and streams. Journal of Chemical Metrology, 13(1), 7-13. google scholar
• Avula, B., Wang, Y. H., Smillie, T. J., Duzgoren-Aydin, N. S., & Khan, I. A. (2010). Quantitative determination of multiple elements in botanicals and dietary supplements using ICP-MS. Journal of agricultural and food chemistry, 58(16), 8887-8894. https://doi. org/10.1021/jf101598g google scholar
• Berzas, N. J., Rodrguez, F. J., Castaneda, P. G., Rodrguez, F. N. (2002). Determination of sildenafil citrate and its main metabolite by sample stacking with polarity switching using micellar electro-kinetic chromatography. Journal of Chromatography A, 953(1-2), 279-286. https://doi.org/10.1016/S0021-9673(02)00131-0 google scholar
• Bethesda, L. J. (2012). LiverTox: Clinical and Research Information on Drug-Induced liver injury [Internet]. https://www.ncbi.nlm. nih.gov/books/NBK548510/ google scholar
• Bradley, B., Singleton, M., & Lin Wan Po, A. (1989). Bismuth toxicity— a reassessment. Journal of clinical pharmacy and therapeutics, 14(6), 423-441. https://doi.org/10.1111/j.1365-2710.1989.tb00268.x google scholar
• Clemens, S., & Ma, J. F. (2016). Toxic Heavy Metal and Metal-loid Accumulation in Crop Plants and Foods. Annual review of plant biology, 67, 489-512. https://doi.org/10.1146/annurev-ar-plant-043015-112301 google scholar
• Daraghmeh, N., Al-Omari, M., Badwan, A. A., & Jaber, A. M. (2001). Determination of sildenafil citrate and related substances in the commercial products and tablet dosage form using HPLC. Jour-nal of pharmaceutical and biomedical analysis, 25(3-4), 483-492. https://doi.org/10.1016/s0731-7085(00)00512-4 google scholar
• Dolan, S. P., Nortrup, D. A., Bolger, P. M., & Capar, S. G. (2003). Analy-sis of dietary supplements for arsenic, cadmium, mercury, and lead using inductively coupled plasma mass spectrometry. Jour-nal of agricultural and food chemistry, 51(5), 1307-1312. https:// doi.org/10.1021/jf026055x google scholar
• Dural E. (2020). Investigation of the Presence of Sildenafil in Herbal Dietary Supplements by Validated HPLC Method. Turk-ish journal of pharmaceutical sciences, 17(1), 56-62. https://doi. org/10.4274/tjps.galenos.2018.91249 google scholar
• Ernst E. (2002). Toxic heavy metals and undeclared drugs in Asian herbal medicines. Trends in pharmacological sciences, 23(3), 136139. https://doi.org/10.1016/S0165-6147(00)01972-6 google scholar
• European Commission. (2006). Commission regulation (EC) No 1881/2006 of 19 December 2006 setting maximum levels for cer-tain contaminants in foodstuffs. Official Journal of the European Union, L 364, 5-24. google scholar
• Feenstra, J., van Drie-Pierik, R. J., Lacle, C. F., & Stricker, B. H. (1998). Acute myocardial infarction associated with sildenafil. Lancet (London, England), 352(9132), 957-958. https://doi.org/10.1016/ s0140-6736(98)00015-4 google scholar
• Filipov, N. M. (2015). Thallium. In Harbison R.D., Bourgeois M.M., Johnson G.T. (Eds.), Hamilton & Hardy’s Industrial Toxicology (pp. 239-246). New Jersey, USA: John Wiley & Sons Inc. google scholar
• Harikrishna, K., Nagaralli, B. S., & Seetharamappa, J. (2008). Extrac-tive spectrophotometric determination of sildenafil citrate (vi-agra) in pure and pharmaceutical formulations. Journal of Food and Drug Analysis, 16(1), 11-17. google scholar
• Hong, F., Jin, T., & Zhang, A. (2004). Risk assessment on renal dys-function caused by co-exposure to arsenic and cadmium using benchmark dose calculation in a Chinese population. Biomet-als, 17, 573-580. google scholar
• Huang, S. A., & Lie, J. D. (2013). Phosphodiesterase-5 (PDE5) inhibi-tors in the management of erectile dysfunction. Pharmacy and therapeutics, 38(7), 407-419. google scholar
• Kekilli, M., Beyazit, Y., Purnak, T., Dogan, S., & Atalar, E. (2005). Acute myocardial infarction after sildenafil citrate ingestion. Annals of Pharmacotherapy, 39(7-8), 1362-1364. google scholar
• Kessler, A., Sollie, S., Challacombe, B., Briggs, K., & Van Hemelrijck, M. (2019). The global prevalence of erectile dysfunction: a review. BJU international, 124(4), 587-599. https://doi.org/10.1111/bju.14813 google scholar
• Kumar, A., Kumar, A., MMS, C. P., Chaturvedi, A. K., Shabnam, A. A., Subrahmanyam, G., ... & Yadav, K. K. (2020). Lead toxicity: health hazards, influence on food chain, and sustainable remediation approaches. International Journal of Environmental Research and Public Health, 17(7), 2179. https://doi.org/10.3390/ijerph17072179 google scholar
• Lee, J. H., Min, A. Y., Park, O. R., Han, J. H., Yang, Y. J., Kim, H., & Baek, S. Y. (2021). Detection of 94 compounds related to sexual enhancement including sildenafil, tadalafil, vardenafil and their analogues in various formulations of dietary supplements and food samples using HPLC and LC-MS/MS. Food Additives & Con-taminants: Part A, 38(5), 769-781. https://doi.org/10.1080/194400 49.2021.1881623 google scholar
• Lopes Junior, A. C. V., Luz, R. D. C. S., Damos, F. S., Santos, A. S. D., Franco, D. L., & Santos, W. T. (2012). Determination of silde-nafil citrate (Viagra®) in various pharmaceutical formulations by flow injection analysis with multiple pulse amperometric de-tection. Journal of the Brazilian Chemical Society, 23, 1800-1806. https://doi.org/10.1590/S0103-50532012005000047 google scholar
• Madden, E. F., & Fowler, B. A. (2000). Mechanisms of nephrotoxic-ity from metal combinations: a review. Drug and chemical toxicol-ogy, 23(1), 1-12. https://doi.org/10.1081/DCT-100100098 google scholar
• Meyers, L. D., Hellwig, J. P., & Otten, J. J. (Eds.). (2006). Dietary refer-ence intakes: the essential guide to nutrient requirements. National Academies Press. google scholar
• Miller, G. M., & Stripp, R. (2007). A study of western pharmaceuticals contained within samples of Chinese herbal/patent medicines collected from New York City’s Chinatown. Legal Medicine, 9(5), 258-264. https://doi.org/10.1016/j.legalmed.2007.04.001 google scholar
• Moriyasu, T., Shigeoka, S., Kishimoto, K., Ishikawa, F., Nakajima, J., Kamimura, H., & Yasuda, I. (2001). Identification system for silde-nafil in health foods. Yakugaku Zasshi: Journal of the Pharmaceu-tical Society of Japan, 121(10), 765-769. https://doi.org/10.1248/ yakushi.121.765 google scholar
• Nielsen, F. H. (1997). Boron in human and animal nutrition. Plant and Soil, 193(1-2), 199-208. google scholar
• Nielsen, S. P. (2004). The biological role of strontium. Bone, 35(3), 583-588. https://doi.org/10.1016/j.bone.2004.04.026 google scholar
• Oh, S. S., Zou, P., Low, M., & Koh, H. (2006). Detection of sildenafil an-alogues in herbal products for erectile dysfunction. J Toxicol Envi-ron Health A, 69(21), 1951-1958. Doi:10.1080/15287390600751355 google scholar
• Raab, A., Stiboller, M., Gajdosechova, Z., Nelson, J., & Feldmann, J. (2016). Element content and daily intake from dietary supple-ments (nutraceuticals) based on algae, garlic, yeast fish and krill oils—should consumers be worried?. Journal of Food Composition and Analysis, 53, 49-60. https://doi.org/10.1016/j.jfca.2016.09.008 google scholar
• Singh, S., Prasad, B., Savaliya, A. A., Shah, R. P., Gohil, V. M., & Kaur, A. (2009). Strategies for characterizing sildenafil, vardenafil, tadalafil and their analogues in herbal dietary supplements, and detect-ing counterfeit products containing these drugs. TrAC Trends in Analytical Chemistry, 28(1), 13-28. https://doi.org/10.1016/j. trac.2008.09.004 google scholar
• Song, F., El-Demerdash, A., & Lee, S. J. (2012). Screening for multiple phosphodiesterase type 5 inhibitor drugs in dietary supplement materials by flow injection mass spectrometry and their quanti-fication by liquid chromatography tandem mass spectrometry. J Pharm Biomed Anal, 70, 40-46. Doi:10.1016/j.jpba.2012.05.017 google scholar
• Tseng, M. C., & Lin, J. H. (2002). Determination of sildenafil ci-trate adulterated in a dietary supplement capsule by LC/MS/ MS. Journal of Food and Drug Analysis, 10(2), 112-119. https://doi. org/10.38212/2224-6614.2759 google scholar
• Tucker, J., Fischer, T., Upjohn, L., Mazzera, D., & Kumar, M. (2018). Unapproved pharmaceutical ingredients included in dietary supplements associated with US Food and Drug Administration warnings. JAMA network open, 1(6), e183337-e183337. google scholar
• Turkish Food Codex. (2011). Türk Gıda Kodeksi Bulaşanlar Yönetmeliği [Turkish Food Codex Contaminants Regula-tion]. Turkish Official Gazette Date: 29.12.2011 Number: 28157 (3.Mükerrer). google scholar
• U.S. EPA. (1994). Method 200.8: Determination of Trace Elements in Waters and Wastes by Inductively Coupled Plasma-Mass Spec-trometry, Revision 5.4. Cincinnati, OH google scholar
• Venhuis, B. J., Blok-Tip, L., & de Kaste, D. (2008). Designer drugs in herbal aphrodisiacs. Forensic Science International, 177(2-3), e25-e27. google scholar
• Voica, C., Roba, C., & Iordache, A. M. (2021). Lithium Levels in Food from the Romanian Market by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS): A Pilot Study. Analytical Letters, 54(1-2), 242-254. https://doi.org/10.1080/00032719.2020.1748642 google scholar
• Wang, W., Xiang, L. Y, Ma, Y. C., Chen, J. W., Peng, L, Gao, X. S.....&Yuan, J. H. (2023). The association between heavy metal exposure and erectile dysfunction in the United States. Asian Journal of An-drology, 25(2), 271-276. google scholar
• Wu, X., Cobbina, S. J., Mao, G., Xu, H., Zhang, Z., & Yang, L. (2016). A review of toxicity and mechanisms of individual and mixtures of heavy metals in the environment. Environmental Science and Pol-lution Research, 23, 8244-8259. https://doi.org/10.1007/s11356-016-6333-x google scholar
• Xiao, L., Zan, G., Qin, J., Wei, X., Lu, G., Li, X., ... & Yang, X. (2021). Combined exposure to multiple metals and cognitive function in older adults. Ecotoxicology and Environmental Safety, 222, 112465. https://doi.org/10.1016/j.ecoenv.2021.112465 google scholar
• Zhu, X., Xiao, S., Chen, B., Zhang, F., Yao, S., Wan, Z., ... & Han, H. (2005). Simultaneous determination of sildenafil, vardenafil and tadalafil as forbidden components in natural dietary supple-ments for male sexual potency by high-performance liquid chro-matography-electrospray ionization mass spectrometry. Journal of Chromatography A, 1066(1-2), 89-95. https://doi.org/10.1016/j. chroma.2005.01.038 google scholar