Sildenafil in Erectile Dysfunction: A Critical Review

Andrea Salonia; Patrizio Rigatti; Francesco Montorsi


Curr Med Res Opin. 2003;19(4) 

In This Article

Pharmacokinetics and Pharmacodynamics

After oral administration, sildenafil is rapidly absorbed with an absolute bioavailability of 40%. The time to peak plasma concentration (Tmax) after oral absorption in the fasting state ranges between 30 and 120 min (median, 60 min), but a high-fat meal increases the Tmax concentration by 60 min and reduces the peak plasma concentration by 29% (there is no effect on area under curve (AUC)). Otherwise, from a clinical point of view, the onset of efficacy is frequently optimal if sildenafil is taken on an empty stomach. The terminal half-life (T_) of sildenafil is 3-5 h.[2,23]

Clinical pharmacokinetics data has identified the formation of a major circulating metabolite of sildenafil, UK-103,320. Sildenafil is subject to an extensive oxidative metabolism in vitro and in vivo, undergoing N-demethylation to UK-103,320, a reaction mediated by the low-affinity, high-capacity P450 (CYP) 3A4 isoenzyme (major route) and the high-affinity, low-capacity CYP2C9 isoenzyme (minor route). Plasma concentrations of UK-103,320 are approximately 40% of those seen for sildenafil and this metabolite contributes to approximately 20% of the net pharmacological effect of sildenafil (UK-103,320 has a 2.5-fold lower in vitro potency for PDE5 than sildenafil).[24,25,26] UK-103,320 has been identified as the major metabolite of sildenafil in mouse, rat, dog and humans.[24,26] The N-demethyl metabolite is modified further, with a terminal phase half-life of approximately 4 h, similar to the parent drug. Approximately 96% of sildenafil and its metabolite are bound to plasma proteins. The reversible binding of sildenafil and its metabolite determines the free active drug available to enter the smooth muscle and inhibit its target enzyme (i.e. PDE5).

Sildenafil is metabolised predominantly at the hepatic level and the UK-103,320 formation is found to be mediated by four cytochromes: CYP3A4, -2C9, -2C19, and -2D6. Estimated relative contributions to net intrinsic clearance are 79% for CYP3A4 and 20% for CYP2C9; for CYP2C19 and -2D6, estimated contributions are less than 2%.[27]

Inherent to its pharmacology, the co-administration of sildenafil and CYP3A4 inhibitors may lead to increased plasma concentration of sildenafil. This may, in turn, lead to enhanced pharmacological and adverse effects (AEs) commonly associated with sildenafil such as headache, flushing, dyspepsia and visual changes.[28,29] Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone and grapefruit juice. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.

It is therefore important to understand the potential for drug interactions with sildenafil. Given the widespread use of sildenafil, it can be co-administered with agents that either directly cause sexual dysfunction or are used to treat diseases associated with sexual dysfunction.[30,31,32]

In HIV patients complaining of ED, the use of sildenafil may incur a possible clinically significant drug interaction with highly active antiretroviral therapy (HAART) due to the potent inhibition of CYP3A4 by protease inhibitors, such as saquinavir, ritonavir, indinavir, nelfinavir and amprenavir and also by the non-nucleoside reverse transcriptase inhibitors such as delavirdine and efavirenz.[33,34] Generally speaking, patients receiving ritonavir (a CYP3A4 and CYP2C9 inhibitor) should not be given sildenafil at doses greater than 25 mg and at a frequency of no greater than once in 48 h.

Sildenafil is widely distributed in tissues but it is predominantly excreted as metabolites in faeces (80%) and urine (13%).[23] In healthy volunteers, after an oral dose of 100 mg of sildenafil, less than 0.001% of the dose was present in the ejaculate 90 min after absorption.[23]

Recently Milligan et al. analysed the pharmacokinetics of sildenafil citrate in ED patients in order to characterise covariate relationships and assist in the development of a rational dosage strategy.[35] A population pharmacokinetics sampling schedule was incorporated into five phase III studies on ED patients. The result of the analyses suggested that the pharmacokinetics of sildenafil in ED patients are consistent with many of the findings obtained from volunteer studies. Features that were common to patient and volunteer data included dose proportionality in sildenafil pharmacokinetics over the range of 25-100 mg with evidence of non-proportionality at higher doses, food-related alteration of sildenafil absorption rate, comparable values for AUC, Cmax, Tmax and t1/2 between patients and volunteers, evidence of reduced sildenafil clearance with hepatic failure, increasing age and co-administration of CYP3A4 potential inhibitors.


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