Population modelling to describe pharmacokinetics of amiodarone in rats: relevance of plasma protein and tissue depot binding.

The objective of this paper was to characterize the disposition phase of AM in rats, after different high doses and modalities of i.v. administration. Three fitting programs, WINNONLIN, ADAPT II and NONMEM were employed. The two-stage fitting methods led to different results, none of which can adequately explain amiodarone's behaviour, although a great amount of data per subject is available. The non-linear mixed effect modelling approach allows satisfactory estimation of population pharmacokinetic parameters, and their respective variability. The best model to define the AM pharmacokinetic profile is a two-compartment model, with saturable and dynamic plasma protein binding and linear tissular depot dynamic binding. These results indicate that peripheral tissues act as depots, causing an important fall in AM plasma levels in the first moment after dosing. Later, the return of the drug from these depots causes a slow increase in serum concentration whenever the dose is reduced.

[1]  M. Lalloz,et al.  Binding of amiodarone by serum proteins and the effects of drugs, hormones and other interacting ligands , 1984, The Journal of pharmacy and pharmacology.

[2]  G. Hollander,et al.  Giving IV and oral amiodarone perioperatively for the prevention of postoperative atrial fibrillation in patients undergoing coronary artery bypass surgery: the GAP study. , 2004, Chest.

[3]  T. Murakami,et al.  Role of organic anion transporting polypeptide 2 in pharmacokinetics of digoxin and beta-methyldigoxin in rats. , 2005, Journal of pharmaceutical sciences.

[4]  G. Naccarelli,et al.  Amiodarone: clinical trials. , 2000, Current opinion in cardiology.

[5]  Douglas L Packer,et al.  Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. , 2005, The New England journal of medicine.

[6]  G. Tognoni,et al.  Clinical Pharmacokinetics of Amiodarone , 1984, Clinical pharmacokinetics.

[7]  A. Auricchio,et al.  New primary prevention trials of sudden cardiac death in patients with left ventricular dysfunction: SCD-HEFT and MADIT-II. , 1999, The American journal of cardiology.

[8]  T. Bouillon,et al.  Population pharmacokinetics of long‐term oral amiodarone therapy , 2000, Clinical pharmacology and therapeutics.

[9]  L. Sheiner,et al.  Estimating bioavailability when clearance varies with time , 1994, Clinical pharmacology and therapeutics.

[10]  H. Yamazaki,et al.  A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[11]  V. Casabó,et al.  Effects of Surfactants on Amiodarone Intestinal Absorption. I. Sodium Laurylsulfate , 1994, Pharmaceutical Research.

[12]  G. Naccarelli,et al.  Amiodarone: What have we learned from clinical trials? , 2000, Clinical cardiology.

[13]  S. Troy,et al.  Population Pharmacokinetics of Intravenous Amiodarone and Comparison with Two‐Stage Pharmacokinetic Analysis , 1997, Journal of clinical pharmacology.

[14]  A. Nácher,et al.  Pharmacokinetic models for the saturable absorption of cefuroxime axetil and saturable elimination of cefuroxime. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[15]  D. Brocks,et al.  Pharmacokinetics of Amiodarone in hyperlipidemic and simulated high fat‐meal rat models , 2005, Biopharmaceutics & drug disposition.

[16]  J. Mason Drug therapy: amiodarone , 1987 .

[17]  S. Shafer,et al.  Use of Population Modeling to Define Rational Monitoring of Amiodarone Hepatic Effects , 2004, Clinical pharmacology and therapeutics.

[18]  M. Kitakaze,et al.  Pharmacokinetic characteristics of amiodarone in long-term oral therapy in Japanese population. , 2005, Biological & pharmaceutical bulletin.

[19]  R. Lledo-Garcia,et al.  Use of nonlinear mixed effect modeling for the intestinal absorption data: application to ritonavir in the rat. , 2005, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[20]  H. Karnes,et al.  Precision, Accuracy, and Data Acceptance Criteria in Biopharmaceutical Analysis , 1993, Pharmaceutical Research.

[21]  K. Williams,et al.  Therapeutic drug monitoring: antiarrhythmic drugs. , 1998, British journal of clinical pharmacology.