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Sildenafil has been reported to cause a clinically significant improvement in the total duration of erections during visual sexual stimulation when evaluated with sexual function questionnaires and Rigiscan devicesBoolell et al 1996Sadovsky et al 2001Because the ejaculatory latency time may be dependent on the duration of erectionany increase in the duration of erection may in turn prolong the ejaculatory latency timeKameya et al 1997In this regardit is recognized that sildenafil may conceivably increase the ejaculatory latency time and contribute to prolongation of ejaculation.
There are several possible mechanisms that can explain the efficacy of sildenafil in the treatment of PESildenafil may inhibit the contractile responses of the seminal vesiclesvas deferensprostateurethraand even the skeletal musclesExpression of PDE activity has been reported in the prostateseminal vesicleand skeletal musclesDjoseland et al 1980Stacey et al 1998Yanaka et al 1998Uckert et al 2001PDE expression in vas deferens has not been studied yethowevernitrergic innervation and nitric oxide synthaseNOSactivity have been localized to the human vas deferensseminal vesicleprostateurethraand skeletal musclesDixon and Jen 1995Jen and Dixon 1995Hedlund et al 1997Jen et al 1997In additionevidence suggests that nitric oxideNOis the predominant inhibitoryrelaxatoryneurotransmitter in the genitourinary organsNaseem et al 2000Andersson 2001In male ratsNO and NO-donator agents were reported to inhibit seminal emissionHull et al 1994FurthermoreNO inhibitors increase the number of ex-copula seminal emissions and decrease the latency to seminal emission in the ratBialy et al 1996
Dapoxetine undergoes rapid absorption and elimination resulting in minimal accumulation and has dose-proportional pharmacokineticswhich are unaffected by multiple dosing and do not vary between ethnic groupsFigure 2Dresser et al2006bDresser et al2004Modi et al2006The pharmacokinetic profile of dapoxetine suggests that it is a good candidate for on-demand treatment of PE.
Dapoxetine is extensively metabolized in the liver by multiple isozymes to multiple metabolitesincluding desmethyldapoxetinedidesmethyldapoxetine and dapoxetine-n-oxidewhich are eliminated primarily in the urineDresser et al2004Modi et al2006Although didesmethyldapoxetine is equipotent to the parent dapoxetineits substantially lower plasma concentrationcompared with dapoxetinelimits its pharmacological activity and it exerts little clinical effectexcept when dapoxetine is coadministered with cytochrome P450 3A4CYP3A4or CYP2D6 inhibitors.
2 Department of UrologyTulane University Health Sciences CenterNew OrleansLAUSA.
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