Factors Affecting the Absorption of Nilvadipine from Disintegration-Controlled Matrix Tablet in Dogs

Abstract

The purpose of this study was to investigate the pharmacokinetics of nilvadipine (NiD) from disintegration-controlled matrix tablets (DCMT). A further purpose was to clarify biological factors that affect the absorption of NiD from DCMT. Two DCMT formulations, which released approximately 80% of NiD in 6 h (DCMT-M) and 10 h (DCMT-S) in vitro, were prepared and compared with immediate-release (IR) tablets. The T_max and mean residence time from DCMT-M and DCMT-S were significantly longer than those from IR tablets in fasted dogs. The area under the plasma concentration–time curve (AUC) (0—infinity) from DCMT-M in both fed and fasted dogs and IR tablets were comparable in both fed and fasted dogs, indicating complete drug release and absorption without food effect. In contrast, the AUC from DCMT-S was significantly lower than the AUC from IR tablets in fasted dogs. The AUC from DCMT-S increased in fed dogs, but it was still lower than the AUC from IR tablets. In vivo absorption profiles calculated by deconvolution method suggested that the duration of drug absorption from DCMT-S was prolonged from 6 h in fasted condition to 8 h in fed condition, suggesting longer gastro-intestinal (GI) transit time in fed condition allowed longer drug release duration from DCMT-S. Regional drug absorption was also evaluated using NiD solution. The results indicated NiD was almost completely absorbed from canine jejunum, ileum and colon, indicating drug permeation is not a rate-limiting factor of NiD absorption. Therefore, limited GI transit time is the primary factor that affects the drug release from DCMT and subsequent NiD absorption.