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Pharmacokinetic/Pharmacodynamic Evaluation of a Novel Potassium Channel Opener, SKP‐450, in Healthy Volunteers
Author(s) -
Jang InJin,
Yu KyungSang,
Shon JiHong,
Bae KyunSeop,
Cho JooYoun,
Yi SoYoung,
Shin SangGoo,
Ryu Keun Ho,
Cho YongBaik,
Kim DaeKee,
Yoo Sung Eun
Publication year - 2000
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912700022009512
Subject(s) - pharmacokinetics , pharmacodynamics , crossover study , pharmacology , medicine , impedance cardiography , plasma renin activity , anesthesia , blood pressure , heart rate , placebo , renin–angiotensin system , stroke volume , alternative medicine , pathology
To evaluate the pharmacokinetic/pharmacodynamic characteristics of SKP‐450, a novel K + channel opener, a single blind, randomized, placebo‐controlled, dose‐rising, parallel‐group study was conducted in 28 healthy volunteers. The volunteers were randomly allocated to dosage groups of 50 μg, 100 μg, 200 μg, and 300 μg. Single doses of SKP‐450 were administered orally, after overnight fasting, and serial blood sampling and pharmacodynamic measurements were performed up to 48 hours after the drug was administered. The 200 μg group was further studied for food interactions in a crossover fashion. Drug concentrations in plasma were determined by HPLC. Hemodynamic changes after drug administration were evaluated by serial measurements of blood pressure (BP), pulse rate (PR), cardiac index (CI), and total peripheral resistance (TPR), using computerized impedance cardiography. Changes in plasma renin activity (PRA) and aldosterone concentrations (PAC) were determined 4 and 24 hours after drug administration. Both SKP‐450 and SKP‐818, an active metabolite, showed linear pharmacokinetic characteristics, and food intake did not significantly affect the pharmacokinetic characteristics of either compound. Dose‐related pharmacological effects were obvious for both the 200 μg and 300 μg groups. Hemodynamic parameters related to vasodilation and reflex tachycardia, such as maximum changes in diastolic BP, PR, CI, and TPR, showed significant dose‐dependent changes. The area under the time‐effect curve (AUEC) of the parameters also showed a similar dose‐dependent pattern. The PRA and PAC exhibited significant changes 4 hours after drug administration in the 300 μg group. Adverse effects, such as headaches, were more frequently observed at the higher dose levels. SKP‐450 was generally well tolerated by these normotensive subjects. The antihypertensive efficacy of SKP‐450 needs to be evaluated in hypertensive patients after multiple dosing.