Simultaneous determination of sildenafil and its active metabolite UK-103,320 in human plasma using liquid chromatography–tandem mass spectrometry

Kim, John; Ji, Hye-Young; Kim, Sook Jin; Lee, Hye Won; Lee, Seung‐Seok; Kim, Dong Sung; Yoo, Moohi; Kim, Won

doi:10.1016/s0731-7085(03)00088-8

Cited by 42 publications

(22 citation statements)

References 10 publications

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“…1) are available, but none describes the combination of UPLC-MS/MS with a low-sample volume and its application in neonatal or pediatric pharmacokinetic studies (Eerkes et al, 2002;Al-Ghazawi et al, 2007;Wang et al, 2005;Sheu et al, 2003;Kim et al, 2003). We present the validation results of a method for simultaneous assay of sildenafil and desmethylsildenafil in human plasma after liquid-liquid extraction, using ultra-performance liquid chromatography and tandem mass spectrometry.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous assay of sildenafil and desmethylsildenafil in neonatal plasma by ultra‐performance liquid chromatography–tandem mass spectrometry

Witjes

Ahsman

Nagel

et al. 2009

Biomedical Chromatography

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Sildenafil is used to treat pulmonary hypertension in neonatal and pediatric patients. Pharmacokinetic studies in these patients are complicated by the limited sample volume. We present the validation results of an assay method to quantitate sildenafil and desmethylsildenafil simultaneously in 50 microL of plasma. Deuterated sildenafil was used as an internal standard. After liquid-liquid extraction, analytes were separated on an ultra-performance liquid chromatography (UPLC)-column and quantified via tandem mass spectrometry. The calibration range was linear, with acceptable accuracy and a precision of <15% for both compounds. The lower limits of quantification were 1 ng/mL. Matrix effects were present, but inter-plasma batch variability was under 12%. The method was successfully applied to samples from a pharmacokinetic study into sildenafil pharmacokinetics in neonates, making maximum use of the limited number and amount of plasma samples available.

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Section: Introductionmentioning

confidence: 99%

Simultaneous assay of sildenafil and desmethylsildenafil in neonatal plasma by ultra‐performance liquid chromatography–tandem mass spectrometry

Witjes

Ahsman

Nagel

et al. 2009

Biomedical Chromatography

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“…N-Desmethyl Sildenafil Assay Concentrations of N-desmethyl sildenafil were determined by using a Thermo Fisher Accela LC system (Thermo Fisher Scientific, Yokohama, Japan) coupled to an LTQ-Orbitrap XL ETD system (Thermo Fisher Scientific). Sample preparation was performed using of liquid-liquid extraction as described previously 18,19) with a minor modification. That is, a 200 µL aliquot of reaction sample was mixed with 2 mL of 0.1 M glycine buffer (saturated with NaCl, pH 10.6), and extracted with 5 mL of tert-butyl methyl ether.…”

Section: Methodsmentioning

confidence: 99%

Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil N-Demethylation and Tadalafil Demethylenation

Takahiro

Nakamura

Kohno

et al. 2015

Biological ^|^ Pharmaceutical Bulletin

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The aim of this study was to characterize the kinetics of metabolite formation of the phosphodiesterase type-5 (PDE5) inhibitors sildenafil and tadalafil by CYP3A4, CYP3A5, and CYP3A7 isoforms. The formations of N-desmethyl sildenafil and desmethylene tadalafil were examined using CYP3A supersomes co-expressing human P450 oxidoreductase and cytochrome b 5 . Both sildenafil N-demethylation and tadalafil demethylenation were catalyzed by CYP3A4, CYP3A5, and to a lesser extent by CYP3A7. The kinetics of desalkyl metabolite formation of the two drugs were well fitted to the Hill equation; however, the Hill coefficients (n) suggested CYP3A-mediated negative cooperativity. Next, we analyzed the kinetics with a two binding sites model assuming two reaction steps: reaction 1 with high-affinity and low-capacity metabolism and reaction 2 with low-affinity and high-capacity metabolism. The kinetics of desalkyl metabolite formation were also fitted to the two binding sites model 1) PDE5 inhibitors have been shown to be an effective vasodilator, and have been used widely as a treatment not only for erectile dysfunction, but also for pulmonary arterial hypertension (PAH).2) Sildenafil and tadalafil are orally active inhibitors of PDE5 that are approved for the treatment of PAH in Japan, but their half-life period in the body differs substantially.3,4) That is, sildenafil has a fairly short half-life of about 4-5 h, whereas tadalafil has a long half-life of about 17.5 h in healthy subjects.5,6) The short half-life of sildenafil makes it the drug of choice in patients with more severe cardiovascular disease, allowing early use of supportive treatment if an adverse clinical event occurs. 7) In contrast, tadalafil has the advantage of once a day dosing compared to sildenafil's three times a day dosing, with implications for patient convenience and compliance. 6,8) Therefore, a transition from sildenafil to tadalafil has been frequently tried in stable patients with PAH. 3,8) In humans, sildenafil is eliminated predominantly by hepatic metabolism and is converted to an active metabolite, N-desmethyl sildenafil, with properties similar to the parent drug.9) The N-demethylation by CYP3A is the major route of metabolism of sildenafil in humans 10) (Fig. 1). Recently, Ku et al. 11) showed that both CYP3A4 and CYP3A5 played a significant role in the metabolism of sildenafil using CYP3A supersomes. That is, the intrinsic clearance for N-dealkylation of sildenafil by CYP3A5 and CYP3A4 were 0.09 and 0.07 µL/ min/pmol P450, respectively. 11) They also demonstrated that the mean rate for N-desalkyl metabolite formation from sildenafil was high in human liver microsome preparations with CYP3A5 activity (heterozygous for CYP3A5*1/*3 alleles) compared to those with null CYP3A5 activity (homozygous for CYP3A5*3 allele).11) These results suggested that genetic polymorphism of CYP3A5 at least partly contributes to interindividual variability in the disposition of sildenafil. On the other hand, tadalafil is eliminated predominantly by oxidative me...

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“…Next, Kim et al (2003a) described a LC/MS/MS method using liquid-liquid extraction for the determination of udenafil in human plasma. The method showed sensitivity (2.0 ng/mL) and the suitability of the method was confirmed in the pharmacokinetic study of udenafil in man.…”

Section: Methods Of Analysismentioning

confidence: 99%

“…There are several studies in the literature reporting the determination of sildenafil citrate in pharmaceuticals, plasma samples, herbal drugs or dietary supplements using liquid chromatography (LC) methods (Eerkes et al, 2002;Sheu et al, 2003;Wang et al, 2005;Reepmeyer, Woodruff, 2007;Ortiz et al, 2010;Bartošová et al, 2011;Hasegawa et al, 2012), gas chromatography (GC) (Berzas et al, 2002;Kim et al, 2003a;Man et al, 2009;Strano-Rossi et al, 2010) and capillary electrophoresis (CE) (Qin, Li, 2002;Flores et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A review of analytical methods for the determination of four new phosphodiesterase type 5 inhibitors in biological samples and pharmaceutical preparations

Codevilla

Castilhos

Bergold

2013

Braz. J. Pharm. Sci.

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The introduction of oral phosphodiesterase type 5 inhibitor therapy in 1998 revolutionized the treatment of erectile dysfunction. Erectile dysfunction is the most common sexual problem in men. It often has a profound effect on intimate relationships and quality of life. The analysis of pharmaceuticals is an important part of the drug development process as well as for routine analysis and quality control of commercial formulations. Whereas the determination of sildenafil citrate, vardenafil and tadalafil are well documented by a variety of methods, there are few publications about the determination of udenafil, lodenafil carbonate, mirodenafil and avanafil. The paper presents a brief review of the action mechanism, adverse effects, pharmacokinetics and the most recent analytical methods that can determine drug concentration in biological matrices and pharmaceutical formulations of these four drugs. A introdução da terapia oral com inibidores da fosfodiesterase tipo 5, em 1998, revolucionou o tratamento da disfunção erétil. A disfunção erétil é o problema sexual mais comum em homens. Muitas vezes tem um efeito profundo nas relações íntimas e na qualidade de vida. A análise de produtos farmacêuticos é uma parte importante do processo de desenvolvimento de fármacos, bem como para a análise de rotina e controle de qualidade das formulações comerciais. Enquanto a determinação do citrato de sildenafila, vardenafila e tadalafila está bem documentada por uma variedade de métodos, existem poucas publicações sobre a determinação de udenafila, carbonato de lodenafila, mirodenafila e avanafila. O artigo apresenta uma breve revisão do mecanismo de ação, efeitos adversos, farmacocinética e os mais recentes métodos analíticos, que podem determinar a concentração do fármaco em matrizes biológicas e formulações farmacêuticas destes quatro fármacos.Unitermos: Inibidores da fosfodiesterase tipo 5/determinação/preparações farmacêuticas. Inibidores da fosfodiesterase tipo 5/determinação/matrizes biológicas Métodos analíticos. Disfunção erétil.

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Simultaneous determination of sildenafil and its active metabolite UK-103,320 in human plasma using liquid chromatography–tandem mass spectrometry

Cited by 42 publications

References 10 publications

Simultaneous assay of sildenafil and desmethylsildenafil in neonatal plasma by ultra‐performance liquid chromatography–tandem mass spectrometry

Simultaneous assay of sildenafil and desmethylsildenafil in neonatal plasma by ultra‐performance liquid chromatography–tandem mass spectrometry

Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil N-Demethylation and Tadalafil Demethylenation

A review of analytical methods for the determination of four new phosphodiesterase type 5 inhibitors in biological samples and pharmaceutical preparations

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