Binding of amiodarone by serum proteins and the effects of drugs, hormones and other interacting ligands

Abstract

Amiodarone is chiefly bound to albumin (62.1%) and much of the remainder (33.5%) is carried on a high molecular weight protein, probably beta-lipoprotein. Analysis of data for amiodarone binding to albumin revealed a high affinity primary binding site (Ka 5.6 X 10(6) litre mol-1) with about four secondary sites (average Ka 1.9 X 10(5) litre mol-1). Studies of the binding of amiodarone in serum revealed one type of binding site only with an affinity constant (Ka 4.2 X 10(6) litre mol-1) similar to that of the primary site on albumin. The secondary albumin binding sites do not seem therefore to be utilized in whole serum and the affinity of the lipoprotein must be similar to that of the primary amiodarone binding site on albumin. The effects of a wide range of compounds on albumin binding of amiodarone were examined by equilibrium dialysis. Quinidine, amitriptyline, cephazolin and palmitate decreased albumin-bound [125I]amiodarone. Neither warfarin nor digoxin affected the binding of amiodarone by albumin, thus of the three drugs known to be potentiated by concomitant amiodarone administration, only potentiation of quinidine could be explained by displacement from serum albumin. Rifampicin, frusemide, phenytoin, (-)-adrenaline, bromocresol green, (-)-noradrenaline and bromocresol purple were found to increase binding of [125I]amiodarone by albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

The Influence of Hyperlipoproteinemia on in Vitro Distribution of Amiodarone and Desethylamiodarone in Human and Rat Plasma

“…Given that each of the various classes of lipoproteins differs in the nature of the apoproteins involved in cellular recognition of the lipoprotein particle, it is important to understand into which lipoprotein fraction a drug preferentially associates. Although prior to this study there was some information in the literature indicating that AM could bind to lipoproteins in plasma (3,7), this is the first study to evaluate the intraplasma distribution of AM and its major metabolite (DEA) in lipoprotein fractions, in both NL and HL plasma.…”

“…The highly lipophilic structure of AM (6) might help to explain some of the pharmacokinetic behaviors of this molecule (5). In plasma, AM is extensively bound to circulating proteins (7). The lipoprotein binding of AM has been estimated to comprise 33.5% of its overall protein binding in plasma (7).…”

“…In plasma, AM is extensively bound to circulating proteins (7). The lipoprotein binding of AM has been estimated to comprise 33.5% of its overall protein binding in plasma (7). Due to its extensive metabolism and its low to moderate hepatic extraction ratio of AM, its clearance is largely attributed to plasma protein binding and intrinsic metabolic clearance (3).…”

Risk-Benefit Assessment of Amiodarone in the Treatment of Cardiac Arrhythmias

“…Amiodarone is highly bound to plasma proteins (96%), mainly to albumin, and following oral administration very little drug or metabolite is recovered in the urine Lalloz et al 1984).…”

Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions Involving Inhibitory Metabolite: A Case Study of Amiodarone

“…The reported free fraction of AMIO in plasma is highly variable, ranging from 0.04 to 0.0002 (Lalloz et al, 1984;Veronese et al, 1988). The data generated in house using the RED device (Waters et al, 2008) at 5 mM show that both AMIO and MDEA are highly bound to plasma protein with f u,p , 0.001.…”