[en] Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and membrane type 1-MMP. It has been shown that cyclodextrins (CDs) are able to form inclusion complexes with Ro 28-2653 and to increase its aqueous solubility. The aim of this study is to demonstrate that an increase in Ro 28-2653 solubility, via ternary complex formation, can lead to an increase in the oral bioavailability of this drug. This study shows that a synergistic effect exists between hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and L-lysine. The use of this multicomponent system enabled the preparation of oral and intravenous solutions of Ro 28-2653. In vivo evaluation of the oral solution of the inclusion complex of Ro 28-2653 in comparison with a suspension of the same uncomplexed drug showed a significant (p < 0.05) increase in absolute bioavailability. The area under curve (AUC) and the peak serum concentration (C-max) were approximately 10 times higher than those obtained with the suspension, while the time (T-max) to reach C-max was reduced. Moreover, in vivo administration of Ro 28-2653 solutions highlighted some information about the pharmacokinetic behavior of Ro 28-2653: a long biologic half-life (about 15.5 h) and a small overall volume of distribution (81). (c) 2006 Elsevier B.V. All rights reserved.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Piette, Marie ; Université de Liège - ULiège > Département de pharmacie > Pharmacie galénique
Evrard, Brigitte ; Université de Liège - ULiège > Département de pharmacie > Pharmacie galénique
Frankenne, Francis
Chiap, Patrice ; Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Bertholet, P.
Castagne, Delphine ; Université de Liège - ULiège > Département de pharmacie > Pharmacie galénique et magistrale
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Delattre, Luc ; Université de Liège - ULiège > Département de pharmacie > Département de pharmacie
Piel, Géraldine ; Université de Liège - ULiège > Département de pharmacie > Pharmacie galénique et magistrale
Language :
English
Title :
Pharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions
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