The anomalous pharmacokinetics of amiodarone explained by nonexponential tissue trapping

Conventional pharmacokinetic (PK) concepts fail to describe the long-term pharmacokinetics of the extremely cationic amphiphilic drug amiodarone. A nonclassical model based on the phenomenon of trapping at tissue binding sites with very long release times is presented, which implies that a volume of distribution and a steady-state level cannot be defined. In agreement with clinical PK data available in the literature, the model well describes not only single-dose disposition curves but also the persistently increasing plasma concentration-time curve during long-term treatment (up to 5 years) and the washout curve following cessation of therapy. The novel aspect is a long-tailed tissue residence time distribution which is incorporated into a recirculatory model leaving the initial distribution process and the clearance concept unchanged. The underlying theoretical approach, which is known as "strange or anomalous" kinetics in physical sciences, and the fractal scaling property of the model may enhance our understanding of the PK of extremely hydrophobic xenobiotics.