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 (0.01 mg kg −1) was administered immediately after separation from cardiopulmonary bypass. Arterial blood was sampled over the next 16 h 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 1/2 α ) was 3.9±1.1 min, metabolic half-life ( t 1/2 β ) was 1.9±0.7 h, and elimination half-life ( t 1/2 γ ) was 95.3±15.2 h. Central-compartment volume was 591.0±42.8 ml kg −1, volume distribution was 2689.2±450.6 ml kg −1, and elimination clearance was 27.7±14.7 ml kg −1 min −1. In the pharmacokinetic simulation model, 0.5, 0.75, and 1.0 μg kg −1 min −1 continuous infusion of colforsin daropate produce effective concentration (5–10 ng ml −1) within 30, 20, and 10 min, respectively following administration. An initial active metabolite of decreased rapidly to less than 1.0 ng ml −1 within the first 10 min. A colforsin daropate infusion of 0.7–1.0 μg kg −1 min −1 for 10–20 min followed by 0.5 μg kg −1 min −1 continuous infusion is recommended to produce an effective concentration (5–10 ng ml −1) within 10–20 min and to maintain a therapeutic concentration throughout the administration period after cardiopulmonary bypass.