Sildenafil

Sildenafil is rapidly absorbed orally, with mean absolute bioavailability of about 41% (range 25-63%).⁸ It appears to distribute into tissues,⁹ with a mean steady-state distribution volume of approximately 105 L;⁹ both sildenafil and its main circulating metabolite are about 96% protein-bound, and sildenafil binding is independent of total drug concentration.¹⁰ Hepatic metabolism occurs mainly through CYP3A4 and, to a lesser extent, CYP2C9, with N-demethylation producing an active metabolite that undergoes further metabolism.¹¹ This metabolite has approximately half the parent drug's in vitro PDE5 inhibitory potency, reaches plasma concentrations about 40% of the parent's, and contributes about 20% of its pharmacological activity; in pulmonary arterial hypertension patients receiving 20 mg three times daily, the corresponding figures are about 72% and 36%. Sildenafil is a weak inhibitor of CYP2C19 and CYP2C9 in vitro¹⁰ and an inhibitor of CYP2E1, OATP1B1, and P-glycoprotein. Its terminal elimination half-life is approximately 3-5 hours,¹⁰ while that of its main metabolite is about 4 hours;¹¹ total body clearance is 41 L/h.¹¹ Following oral or intravenous administration, elimination is predominantly as metabolites in feces and less extensively in urine, accounting for approximately 80% and 13% of an administered oral dose, respectively.⁸ Healthy volunteers aged 65 or older showed reduced clearance and approximately 90% higher plasma concentrations of sildenafil and its active metabolite than volunteers aged 18-45, with free sildenafil concentrations approximately 40% higher because of age-related differences in protein binding.¹⁰