Rapid and Sensitive Determination of Udenafil in Plasma by LC-MS/MS for Intranasal Pharmacokinetic Study in Rats

Abstract

A rapid and sensitive analytical method for udenafil in rat plasma was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This chromatographic procedure was then applied to the in vivo pharmacokinetic studies in rats for determining the advantages of intranasal administration of the drug over oral administration. Using liquid-liquid extraction (LLE), udenafil and the internal standard (IS) sildenafil were extracted with dichloromethane from 100 m ml of plasma samples. Chromatographic separation was performed using Pursuit XRS C 18 column (50 mm؋2.1 mm, i.d., 3 m mm, Varian Inc., CA, U.S.A.) with an isocratic mobile phase consisting of acetonitrile and 10 mM ammonium acetate (90 : 10, v/v) at a flow rate of 0.2 ml/min over a total run time of 2.5 min. Detection and quantification was performed by mass spectrometry using the multiple reaction-monitoring mode at m/z 517.4→283.1 for udenafil and m/z 475.3→100.0 for IS. Results showed that the developed method was sensitive and specific for udenafil. Linearity was obtained in the range of 0.5-1000 ng/ml. The coefficient of variation of both intra-and inter-day validation were below 11.6% and the intraand inter-day accuracy ranged from 91.5 to 109.9%. Udenafil concentration was successfully measured from plasma after intranasal as well as after intravenous or oral administration at clinical dose (1.67 mg/kg) in rats. Moreover, the T max values obtained from pharmacokinetic studies suggested that administration of udenafil intranasally could be more effective than by the oral route.

Enhanced Bioavailability of Tadalafil after Intranasal Administration in Beagle Dogs

“…Previous studies of sildenafil and udenafil showed shorter T max values and a higher exposure for the intranasal versus oral administration [12,13,21]. Similarly, in this study, the pharmacokinetic tadalafil exposure after intranasal administration was significant higher than after oral administration.…”

“…The pharmacokinetics of the PDE5 inhibitors using various administration routes have previously been assessed in animals and humans [5,7,8,9,10,12,13,21]. Particularly, the intranasal delivery of PDE5 inhibitors has been highlighted because of its advantages [22].…”

“…In order to meet patients’ needs, various formulations have been investigated, including orodispersible formulations, orally disintegrating film formulations, and transdermal patches [5,7,8,9,10,11]. In addition, the pharmacokinetics of sildenafil and udenafil have been investigated, following intranasal administration in animals [12,13]. Relative to oral administration, intranasal administration has several advantages, including a fast onset of effectiveness due to rapid absorption, avoidance of intestinal and hepatic first-pass effects, greater bioavailability allowing for lower doses, a reduction in gastrointestinal disturbances, a reduced risk of overdose, non-invasive administration, ease of convenience and self-medication, and improved patient compliance [14,15,16].…”

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

“…This method was successfully applied to a pharmacokinetic study of udenafil 100 mg in healthy Korean male volunteers. Ku et al (2011) described a more sensitive and rapid analysis of udenafil in rat plasma, using an LC-MS/ MS system, aiming to replace the previous methods. The authors justify their work due to the large plasma volume used, long retention times and because pharmacokinetic studies in animal model had to be conducted at high doses considering the low limit of quantification of the methods previously published (Shim et al, 2002;Cho et al, 2003;Kim et al, 2003b, Bae et al, 2008.…”