Naslov
Admet Evaluation of Phosphodiesterase Type 5 Inhibitors Found in Adulterated Dietary Supplements - In Silico Study

Autori
Jadrijević-Mladar Takač, Milena ; Žuntar, Irena ; Krivohlavek, Adela ; Takač, Tin

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Final Programme & Book of Abstracts 3rd International Symposium on Scientific and Regulatory Advances in Biological and Non- Biological Complex Drugs: A to Z in Bioequivalence, SRACD 2018 / Klebovich, Imre ; Shah, Vinod P. ; Mühlebach, Stefan - Veszprém, 2018, 118-118

ISBN
978-615-5270-50-5

Skup
3rd International Symposium on Scientific and Regulatory Advances in Biological and Non- Biological Complex Drugs: A to Z in Bioequivalence, SRACD 2018

Mjesto i datum
Budimpešta, Mađarska, 12.11.2018. - 14.11.2018

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
phophodiesterase type 5 inhibitors (PDE5Is) ; sildenafil analogues ; food supplement ; safety ; ADMET

Sažetak
The popularity and interest in phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction (ED) has led to the increase in prevalence of illicit food supplements with these drugs. Structural analogues of the registered ED drugs sildenafil, tadalafil, and vardenafil were identified as the main adulterants. More than fifty analogues have been reported in the literature and it is expected that their use in seemingly harmless food supplements may cause serious adverse effects.The aim of this in silico study was to evaluate ADMET properties of phosphodiesterase 5 inhibitors (PDE5Is) including sildenafil and its analogues and to predict their safety profile by ADMET PredictorTM (SimulationsPlus Inc., USA) in order to highlight their potential impact on health. Based on ADMET Predictor analysis the following risks with corresponding computed scores were revealed: ADMET_Risk 1.013-9.644, Absn_Risk 0.000-5.568, CYP_Risk 0.000-3.641, MUT_Risk 0.0-1.0, and TOX_Risk 0.000-1.086. All investigated molecules (n=11) are characterized with relatively high molecular weight (MW 439.518-1035.218) and with relatively low lipophilicity (MlogP -0.614-1.591). The main risk in physicochemical part that reflect on overall absorption revealed water solubility (S+Sw 0.018-0.562). Among all predicted ADMET risk codes, the size of molecules, charge and permeability prevail over CYP3A4 clearance, hydrogen bond acceptors, rotatable bonds, as well as mouse (Xm) and rat (Xr) carcinogenicity. For mirodenafil and morfolinoacetidenafil, both, Xm and Xr were predicted, and for acetilenafil and hydroxyacetildenafil only Xm and for lodenagil carbonate only Xr was predicted. The cardiotoxicity (TOX_hERG) was predicted for aildenafil. For five investigated PDE5Is no TOX_Risk was computed (sildenafil, homosildenafil, hydroxyhomosildenafil, vardenafil, udenafil). However, the low TOX_MUT score 1 has been predicted for sildenafil, homosildenafil, hydroxyhomosildenafil, mirodenafil and aildenafil. All these drugs are extensively metabolized by CYP enzymes (CYP 2C8, 2D6 and 3A4) and all of them are CYP 3A4 inhibitors. PDE5Is in clinicl use are safe drugs for ED treatment. However, the results of this study revealed that in addition to potential carcinogenicity of some investigated PDE5Is present in food supplements, their CYP 3A4 inhibition could contribute to drug-drug and drug-food interactions, and the most unfavourable safety profile was predicted for mirodenafil.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Javno zdravstvo i zdravstvena zaštita, Farmacija

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