A recirculatory model with enterohepatic circulation by measuring portal and systemic blood concentration difference.

Abstract

The present study describes a recirculatory model for the evaluation of pharmacokinetic characteristics of drugs possessing enterohepatic circulation (EHC). The advantage of the model is to separately define the extent and rate of absorption for the dosage and EHC after oral administration. Cephradine was used as a model drug and was intravenously or orally administered to rats. Portal and systemic bloods were simultaneously collected in order to estimate various local moments after defining the global moments obtained by non-compartment analysis. For the zero-order moments, bioavailability (BA), the hepatic recovery ratio (Fh), the sum of the local absorption ratio for the dosage and recirculatory local absorption ratio for EHC (F(a)po), and the recirculatory local absorption ratio for EHC (F(a)ehc) after oral administration were estimated to be 95.6, 77.9, 172, and 71.5%, respectively. These data indicate that a complete absorption and substantial EHC contribute high oral exposure of cephradine. For the first-order moments, the sum of the mean local absorption times for the dosage and EHC (t(a)po) and the mean transit time for a single pass of EHC (tc) were 2.50 and 0.117 hr, suggesting a rapid EHC of cephradine compared with the absorption from the dosage. With this model, the absorption rate-time profiles for the dosage and EHC were separately simulated by using a program of nonlinear least squares (MULTI) with fast inverse Laplace transform (FILT). The cumulative biliary excretion ratio (Fbile) calculated by the model was in good agreement with the experimental value obtained in the bile ductcannulated rats. These results suggest that the model proposed in this study would be useful for evaluating the extent and rate of ECH along with absorption from the dosage after oral administration of drugs.