Pharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions.
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 (Cmax) were approximately 10 times higher than those obtained with the suspension, while the time (Tmax) to reach Cmax 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 15.5h) and a small overall volume of distribution (8l).
Piette
Marie
M
Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Liège, CHU, B36, B-4000 Liège 1, Belgium. Marie.Piette@ulg.ac.be
Evrard
Brigitte
B
Frankenne
Francis
F
Chiap
Patrice
P
Bertholet
Pascal
P
Castagne
Delphine
D
Foidart
Jean-Michel
JM
Delattre
Luc
L
Piel
Géraldine
G
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000737:chemistry*; D007275:Injections, Intravenous; D008239:Lysine / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012756:Sheep; D012995:Solubility; D012996:Solutions; D013535:Suspensions; D047392:beta-Cyclodextrins / Q000737:chemistry*
D005079:Excipients; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; C453902:Ro 28-2653; D012996:Solutions; D013535:Suspensions; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D008239:Lysine