Pharmacokinetics and a simulation model of colforsin daropate, new forskolin derivative inotropic vasodilator, in patients undergoing coronary artery bypass grafting.

Abstract

Colforsin daropate, a water-soluble forskolin derivative, is an adenyl cyclase activator with positive inotropic and vasodilatory effects that are useful in the treatment of ventricular dysfunction. We investigated the pharmacokinetics of colforsin daropate in cardiac surgery patients and performed simulations to determine the dosage necessary to maintain an effective plasma concentration following cardiopulmonary bypass. In six patients undergoing coronary artery bypass graft, colforsin daropate (0.01mgkg(-1)) was administered immediately after separation from cardiopulmonary bypass. Arterial blood was sampled over the next 16h and plasma concentrations of colforsin daropate and its initial active metabolite were determined by gas-chromatography. Extended nonlinear least-squares regression was used to fit a three-compartment model to each patient's data. Distribution half-life (t(1/2alpha)) was 3.9+/-1.1min, metabolic half-life (t(1/2beta)) was 1.9+/-0.7h, and elimination half-life (t(1/2gamma)) was 95.3+/-15.2h. Central-compartment volume was 591.0+/-42.8mlkg(-1), volume distribution was 2689.2+/-450.6mlkg(-1), and elimination clearance was 27.7+/-14.7mlkg(-1)min(-1). In the pharmacokinetic simulation model, 0.5, 0.75, and 1.0microgkg(-1)min(-1) continuous infusion of colforsin daropate produce effective concentration (5-10ngml(-1)) within 30, 20, and 10min, respectively following administration. An initial active metabolite of decreased rapidly to less than 1.0ngml(-1) within the first 10min.A colforsin daropate infusion of 0.7-1.0microgkg(-1)min(-1) for 10-20min followed by 0.5microgkg(-1)min(-1) continuous infusion is recommended to produce an effective concentration (5-10ngml(-1)) within 10-20min and to maintain a therapeutic concentration throughout the administration period after cardiopulmonary bypass.

• Authors: Mutsuhito Kikura, Koji Morita, Shigehito Sato
• Journal: Pharmacological research (Pharmacol Res) Vol. 49 Issue 3 Pg. 275-81 (Mar 2004) ISSN: 1043-6618 [Print] Netherlands
• PMID: 14726224 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• colforsin daropate
• Colforsin

Topics

• Aged
• Angina Pectoris (blood, drug therapy, surgery)
• Cardiotonic Agents (blood, pharmacokinetics, therapeutic use)
• Colforsin (analogs & derivatives, blood, pharmacokinetics, therapeutic use)
• Coronary Artery Bypass (methods)
• Dose-Response Relationship, Drug
• Female
• Humans
• Injections, Intravenous
• Least-Squares Analysis
• Male
• Middle Aged
• Models, Biological
• Vasodilation (drug effects, physiology)