Advancing topical administration of sildenafil toward clinical translation: ex vivo glans permeation and pilot human pharmacokinetics
Abstract
Sildenafil citrate, a selective phosphodiesterase type 5 (PDE5) inhibitor, is widely used to treat erectile dysfunction; however, its oral administration is associated with systemic adverse effects and reduced bioavailability due to first-pass metabolism. This study evaluated the potential for the topical delivery of sildenafil to the glans in the form of a cream formulation. In vitro permeation assays on bull glans tissue, which lacks a stratum corneum, showed that the tested formulation achieved moderate permeation (17.2 ± 1.61 µg/cm2) and tissue retention (382 ± 80.5 µg/cm2), supporting its suitability for subsequent in vivo testing. A pilot study in healthy male volunteers (n = 8) demonstrated low but detectable salivary sildenafil concentrations following topical application, with mean concentrations rising initially and then remaining relatively stable over the 2-4 h observation period. Population pharmacokinetic modelling using a one-compartment model with first-order absorption and elimination yielded an absorption rate constant of ka = 1.20 h⁻1 and a model-derived tmax of approximately 1.9 h. Absolute salivary concentrations remained in the low ng/mL range, indicating limited systemic exposure. Histological analysis confirmed close structural similarity between bull and human glans tissue, supporting the translational relevance of the ex vivo model. Overall, these findings support the feasibility of developing a locally acting topical alternative to oral PDE5…
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