Pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, in spontaneously or DOCA-salt-induced hypertensive rats

Hypertension is the most common comorbidity and major risk factor in patients with erectile dysfunction. The pharmacokinetics of mirodenafil, used for the treatment of erectile dysfunction, after the intravenous and oral administration (20 mg/kg) to 6-week-old rats (with blood pressure within the normotensive range) and 16-week-old spontaneously hypertensive rats (SHRs) and their age-matched control normotensive Kyoto-Wistar (KW) rats, and 16-week-old deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats) and their age-matched control Sprague-Dawley (SD) rats were compared. It was found that time-averaged renal clearance (Cl_r) was of minor importance and that time-averaged non-renal clearance (Cl_nr) was dominant. In both 6- and 16-week-old SHRs, the Cl_nrs and areas under the curve (AUCs) of intravenous mirodenafil were significantly smaller and greater than those of the controls, but in 16-week-old DOCA-salt rats, they were comparable to the controls. Although the AUC of oral mirodenafil in 16-week-old SHRs was comparable to the controls, the Cl_nrs (or total body clearances, Cls) of intravenous mirodenafil and intestinal intrinsic clearances were significantly smaller than the controls and comparable to the controls for both 6- and 16-week-old SHRs, unlike in the 16-week-old DOCA-salt rats. The above data suggest that the significantly smaller Cl_nr and greater AUC of intravenous mirodenafil and comparable AUC of oral mirodenafil in 16-week-old SHR could be due to the hereditary characteristics of SHRs, and not due to the hypertensive state itself.