Phosphodiesterase-5 (PDE-5) Inhibitors as Emergent Environmental Contaminants: Comparison
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by laura scrano.

Erectile dysfunction (ED) is an increasing disorder [16], affects 25 to 35 million men over 18 years in Europe. Pharmaceuticals used to reduce this disorder act as phosphodiesterase-5 (PDE-5) inhibitors, a family of enzymes typically active in cyclic guanosine monophosphate (cGMP) degradation. The inhibition of PDE-5 results in the intracellular accumulation of cGMP, which plays a central role in signal transduction and regulates several physiological responses.

  • phosphodiesterase-5 (PDE-5) inhibitors
  • environment contamination
  • analytical methods

1. Introduction

Emerging pollutants (EPs) are synthetic or naturally occurring compounds not commonly examined in the environment [1]. Still, they can enter ecosystems and cause recognised or supposed adverse effects on ecology and human health [1]. Moreover, they undergo chemical/biological transformations, forming by-products sometimes more toxic than the parent molecules. The final issue is the accumulation of original and transformed substances in water bodies [2]. In particular, Zuccato et al. [3] evidenced the presence in ground and surface waters of drugs and pharmaceuticals having polar structures, probably coming from WWTP effluents.
When absorbed by the body, a pharmaceutical substance enters the circulation and distributes to reach the target site to perform its function [2,4][2][4]. When the metabolism process is activated, some molecules reach the target site and others transform into inactive metabolites, which are substances no longer producing effects into the body. Many medicines, however, are excreted without being metabolised or at least without being completely inactivated [2,5][2][5]. These, together with sewage, reach the WWTP, where organic loads degrade and water is purified. Unfortunately, these structures are often not designed to degrade active substances of pharmaceutical origin, which, therefore, once again manage to resist, unharmed, and maintain their effectiveness. As a result, the purified water (still rich in active ingredients) flows into the receiving channels, carrying a load of pollutants to rivers and lakes. Thus, tons of active substances such as antibiotics, anti-neoplastic, estrogens and others are poured into surface waters [6,7][6][7]. Once in the environment, the drug eventually degrades or can persist very long, resulting in noticeable build-ups [8]. In the sediments of some Italian rivers such as the Po, Lambro and Adda rivers, as well as in the aqueducts of the towns of Varese and Lodi, traces of various drugs were present in different amounts, including antibiotics (lincomycin and erythromycin), anticancer (cyclophosphamide), anti-inflammatory (ibuprofen), diuretics (furosemide) and antihypertensive (atenolol) drugs [9]. The existence of these compounds in environmental systems is of concern since they constitute a complex assortment, which could induce the occurrence of undesirable synergistic effects and could be responsible for many health adverse effects such as allergies, development of antibiotic-resistance phenomena, disorders of the endocrine system, cytolytic or cytostatic effects and others [10,11,12][10][11][12].

2. Source of PDE-5 Inhibitors in the Environment

According to the “anatomical therapeutic and chemical” (ATC) classification system, PDE-5 inhibitors are available in the class ATC code G04BE. The four most significant inhibitors used are sildenafil (Viagra®), tadalafil (Cialis®), vardenafil (Levitra®) and avanafil (Spedra®), all approved by Food and Drug Administration (FDA). In addition, there are other pharmaceuticals that are non-FDA approved and commercially available in some countries, such as udenafil (Zydena®) in South Korea and Malaysia, mirodenafil (Mvix®) in South Korea and lodenafil carbonate (Helleva®) in Brazil [28][13]. Sildenafil (C22H30N6O4S) was discovered in 1989 by the Pfizer Cardiovascular Research and Development Group (Sandwich, Kent, UK) during research focused on identifying PDE-5 inhibitors to treat angina pectoris due to the abundant presence of the PDE-5 enzymes in platelets and vascular smooth muscle cells. It showed low effectiveness on angina pectoris tests and penile erection as the primary collateral effect [29][14]. The FDA, in 1998, approved sildenafil for erectile dysfunction treatments and then in 2005, the European Medicine Agency (EMA) approved it for class II and class III pulmonary hypertension treatments. Vardenafil (C23H32N6O4S) and tadalafil (C22H19N3O4) were introduced clinically in 2003, while avanafil (C23H26ClN7O3) in 2013. Although the structural differences between these compounds are minor, they have different pharmacokinetic properties (absorption, distribution, metabolism and excretion). In addition, they can exert their activity also on other PDE-types, as reported in Table 1 [30][15].
Table 1. Pharmacokinetic parameters of PDE-5 inhibitors (re-edited from [15]).
Parameters/DrugsSildenafil (Viagra)Vardenafil (Levitra)Tadalafil (Cialis)Avanafil (Spedra)
Bioavailability41% (mean)

25–63% (range)
15% (mean)--
Tmax1 h (median)

0.5–2 h (range)
1 h (median)

0.5–2 h (range)
2 h (median)


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