Pharmacokinetics and antihypertensive effect of oral pelanserin in renal hypertensive dogs

The pharmacokinetics and antihypertensive effect of pelanserin (CAS 2208-51-7), a 5-HT₂- and α₁-antagonist, were studied during repetitive administration (0.5 mg/kg, p.o., b.i.d.) in renal hypertensive dogs. After the first dose, pelanserin was absorbed reaching a C(max) value of 39.6 ± 9.01 ng/ml at a t(max) of 2.58 ± 0.74 h. The steady state of plasma levels was reached between the 3rd and 15th doses of pelanserin. Pharmacokinetic parameters calculated after the 47th dose of pelanserin were C(max)ss of 147.15 ± 35.88 ng/ml at a t(max)ss of 3.17 ± 1.02 h, AUC(0-12h) of 593.80 ± 106.96 ng·h/ml and a terminal half-life of 18.02 ± 2.94 h. The accumulation ratio determined as C(min)ss/C(min)1 was 2.36 ± 0.43 and was similar to that calculated in basis to the terminal half-life 2.67 ± 0.37. On the other hand, pelanserin produced blood pressure decrease with two different profiles. After the first dose an acute antihypertensive effect was observed which reached a maximum of 20 mmHg in about 3 h; then blood pressure recovered gradually arriving to basal values at 12 h. When administered repetitively, pelanserin produced a gradual reduction in blood pressure which reached its maximum at 15 days. After the last dose, blood pressure basal values were about 20 mmHg lower than pretreatment levels and remained almost unchanged during 48 h after the last dose. It is concluded that pelanserin pharmacokinetic and pharmacodynamic profiles in dogs are adequate for an antihypertensive agent, therefore this drug possesses potential therapeutic usefulness in the treatment of hypertension.