| Reference | [1]. Drug Test Anal. 2014 Jun;6(6):552-62. doi: 10.1002/dta.1564. Epub 2013 Dec 6.<br />
Metabolism of aildenafil in vivo in rats and in vitro in mouse, rat, dog, and human liver microsomes.<br />
Li Y(1), Wu L, Gu Y, Si D, Liu C.<br />
Author information: (1)Shenyang Pharmaceutical University, Shenyang, 110016, China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China.<br />
Aildenafil, 1-{[3-(6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d] primidin-5-yl)-4-ethoxyphenyl] sulfonyl}-cis-3, 5-dimethylpiperazine, a phosphodiesterase type V enzyme inhibitor (PDE5I), is under development for treatment of erectile dysfunction (ED). The purpose of this study was to elucidate metabolism of aildenafil in vivo in rats and in vitro in mouse, rat, dog, and human liver microsomes. Thirty-one phase I metabolites have been found by LTQ/Orbitrap hybrid mass spectrometry in rat urine, faeces, and bile after oral administration. Major biotransformation pathways of aildenafil included N-dealkylation of the piperazine ring, hydroxylation and dehydrogenation, aliphatic hydroxylation and loss of alkyl group of piperazine ring. Minor pathways involved hydroxylation on the phenyl ring, pyrazole N-demethylation, O-deethylation, loss of piperazine ring (cleavage of N-S bond) and dehydrogenation on the piperazine ring. Similar metabolic pathways of aildenafil were observed in the incubations of liver microsomes from mouse, rat, and dog as well as from human. The depletion rate of parent drug in mouse and rat liver microsomes was significantly different from that in human liver microsomes. The cytochrome P450 reaction phenotyping analysis was conducted using isozyme-specific inhibitors. The results indicated that CYP3A was the main isoenzyme involved in oxidative metabolism of aildenafil. Overall, these in vitro and in vivo findings should provide valuable information on possible metabolic behaviours of aildenafil in humans.<br />
DOI: 10.1002/dta.1564 PMID: 24311535 [Indexed for MEDLINE]<br />
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[2]. J Pharm Biomed Anal. 2011 Mar 25;54(4):735-41. doi: 10.1016/j.jpba.2010.11.020. Epub 2010 Nov 21.<br />
The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: a Viagra with a pop.<br />
Venhuis BJ(1), Zomer G, Hamzink M, Meiring HD, Aubin Y, de Kaste D.<br />
Author information: (1)National Institute for Public Health and the Environment, Center for Quality of Chemical-Pharmaceutical Products, Anthonie van Leeuwenhoeklaan 9, Bilthoven, The Netherlands. [email protected]<br />
A new unapproved analogue of sildenafil was detected in capsules of a herbal dietary supplement promoted as a libido enhancing product. Using LC-DAD-MS, MS-MS, HRMS, IR and NMR the analogue was shown to be a derivative of the PDE-5 inhibitor aildenafil with a nitrosamine moiety. A hydrolysis experiment showed that the new analogue was a prodrug of aildenafil and was therefore named nitroso-prodenafil. A capsule contained 108 mg of nitroso-prodenafil which is equivalent to 84 mg of aildenafil and 5.1 mg of nitrogen monoxide (NO). Although it is unknown how much NO can be usefully generated there is 3-fold more NO present than in a 10 mg isorbide nitrate tablet. Both PDE-5 inhibitors and nitrosamines cause vasodilatation by increasing levels of NO. To their coincidental use is warned against because it may cause a fatal drop in blood pressure. In addition, nitrosamines are known carcinogens. This is the first time a PDE-5 inhibitor and a potential NO donor were identified in one molecule. The findings indicate the dangerous level of advancement in medicinal chemistry by producers of unapproved drugs.<br />
DOI: 10.1016/j.jpba.2010.11.020 PMID: 21145686 [Indexed for MEDLINE]<br />
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[3]. J Pharm Biomed Anal. 2014 Sep;98:153-9. doi: 10.1016/j.jpba.2014.05.029. Epub 2014 May 28.<br />
Structural elucidation of propoxyphenyl isobutyl aildenafil, adulterant in a health supplement using high-resolution Orbitrap mass spectrometry.<br />
Kee CL(1), Koh HL(2), Bloodworth BC(3), Zeng Y(3), Kiang KH(3), Low MY(3), Ge X(3).<br />
Author information: (1)Pharmaceutical Laboratory, Applied Sciences Group, Health Sciences Authority, 11 Outram Road, Singapore 169078, Singapore. Electronic address: [email protected]. (2)Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. (3)Pharmaceutical Laboratory, Applied Sciences Group, Health Sciences Authority, 11 Outram Road, Singapore 169078, Singapore.<br />
A new sildenafil analogue, propoxyphenyl isobutyl aildenafil has been found in trace quantity from one health supplement. It has been purified by preparative high performance liquid chromatography (HPLC). The structural elucidation of this compound has been carried out using high-resolution Orbitrap mass spectrometry under two fragmentation modes, namely High energy Collision Dissolution (HCD) and Collision Induced Dissolution (CID). Under MS(3) experiments and CID mode, the isobutyl-bonded fragments of propoxyphenyl isobutyl aildenafil at m/z 313 and 297 have been compared with the reference ions derived from isobutyl sildenafil. The accurate mass measurement of each product ions has been carried out with the aid of Mass Frontier software (version 5.0). The mass error of all product ions is not more than 5.0ppm.<br />
DOI: 10.1016/j.jpba.2014.05.029 PMID: 24922086 [Indexed for MEDLINE]<br />
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[4]. J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Jul 15;931:111-6. doi: 10.1016/j.jchromb.2013.05.013. Epub 2013 May 24.<br />
Determination of sildenafil, vardenafil and aildenafil in human plasma by dispersive liquid-liquid microextraction-back extraction based on ionic liquid and high performance liquid chromatography-ultraviolet detection.<br />
Xiao C(1), Tang M, Li J, Yin CR, Xiang G, Xu L.<br />
Author information: (1)Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.<br />
A novel method which involved dispersive liquid-liquid microextraction (DLLME)-back extraction based on ionic liquid (IL) was developed for the determination of three phosphodiesterase-5 (PDE-5) inhibitors, sildenafil (SD), vardenafil (VD) and aildenafil (AD), in human plasma. DLLME based on IL as the extractant solvent and methanol as the dispersive solvent was the first step to extract PDE-5 inhibitors from sample solution; the other step of back extraction was followed by transferring target analytes from the IL to acidified aqueous solution. This two-step extraction ensured the compatibility of the final extractant phase, acidified aqueous solution herein, with the reversed phase high performance liquid chromatography-UV detection, and afforded clean extractant phase. The optimal extraction condition was obtained after systematical optimization. The sample solution (960μL) was extracted by 20μL of 1-octyl-3-methylimidazolium hexafluorophosphate in the presence of 20μL methanol and 300mgmL(-1) NaCl with the assistance of vortex; IL phase enriched with the target analytes was then extracted by 10% acetic acid aqueous solution. Good linearity ranges (SD 1-500ngmL(-1), VD 2-2000ngmL(-1) and AD 2-2000ngmL(-1)) with suitable r(2) (=0.9999) were achieved. Limits of detection (LODs) in pure water were 0.15ngmL(-1), 0.30ngmL(-1) and 0.43ngmL(-1) for VD, SD and AD, respectively. Intra-day and inter-day relative standard deviations were below 6.38%. Finally, this method was applied for the determination of PDE-5 inhibitors in human plasma with satisfactory LODs of 0.92ngmL(-1), 1.19ngmL(-1) and 2.69ngmL(-1) for VD, SD and AD, respectively. Acceptable absolute recoveries were obtained from 100.4% to 103.9%. The developed method afforded a convenient, fast and cost-saving operation with high extraction efficiency for the test analytes. It has potential to be applicable to biological samples.<br />
DOI: 10.1016/j.jchromb.2013.05.013 PMID: 23774245 [Indexed for MEDLINE]<br />
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[5]. J Pharm Biomed Anal. 2007 May 9;44(1):231-5. doi: 10.1016/j.jpba.2007.01.017. Epub 2007 Jan 17.<br />
Liquid chromatography tandem mass spectrometry assay to determine the pharmacokinetics of aildenafil in human plasma.<br />
Wang J(1), Jiang Y, Wang Y, Zhao X, Cui Y, Gu J.<br />
Author information: (1)Research Center for Drug Metabolism, College of Life Science, Jilin University, Changchun 130023, China.<br />
A simple, sensitive and specific liquid chromatography/tandem mass spectrometry method for the quantitation of aildenafil, a new phosphodiesterase V inhibitor, in human plasma is presented. The analyte and internal standard, sildenafil, were extracted by a one-step liquid-liquid extraction in alkaline conditions and separated on a C(18) column using ammonia:10mM ammonium acetate buffer:methanol (0.1:15:85, v/v/v) as the mobile phase. The detection by an API 4000 triple quadrupole mass spectrometer in multiple-reaction monitoring mode was completed within 2.5 min. The calibration curve exhibited a linear dynamic range of 0.05-100 ng/ml with a 10 pg/ml limit of detection. The intra- and inter-day precisions measured as relative standard deviation were within 8.04% and 5.72%, respectively. This method has been used in a pharmacokinetic study of aildenafil in healthy male volunteers each given an oral administration of one of the three dosages.<br />
DOI: 10.1016/j.jpba.2007.01.017 PMID: 17306493 [Indexed for MEDLINE]
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