Separate Evaluation of Fraction Absorbed and Intestinal Availability after Oral Administration of Drugs Based on the Measurement of Portal and Systemic Plasma Concentrations and Luminal Concentration.

Abstract

There are several experimental methods to estimate the product of the fraction absorbed (Fa) and intestinal availability (Fg) in vivo after oral administration of drugs. Metabolic enzyme inhibitors are typically used to separate Fg from Fa·Fg. Since Fa·Fg can be regarded as Fa under metabolism-inhibited conditions, Fg can be isolated by dividing Fa·Fg by Fa. However, if the inhibition of intestinal metabolism is insufficient, Fa is overestimated, which results in an underestimation of Fg compared to the actual value. In this study, to avoid this problem, an experimental method for the separate estimation of Fa and Fg in rats without utilizing metabolic enzyme inhibitors was established. Buspirone, a CYP3A substrate, and ribavirin, a substrate of purine nucleoside phosphorylase and adenosine kinase, were selected as models. Following oral administration of the drugs with fluorescein isothiocyanate dextran 4000 (FD-4, an unabsorbable marker), Fa·Fg was pharmacokinetically calculated from portal and systemic plasma concentration-time profiles of model drugs and Fa was calculated from the difference in the ileal concentration profiles of the drugs and FD-4. Fg was evaluated by dividing Fa·Fg by Fa. Following oral administration, buspirone was not detected in any segment of the small intestine, indicating that the administered buspirone was completely absorbed. In addition, buspirone was extensively metabolized in enterocytes (Fg = 20.1). Ribavirin was primarily absorbed in the upper segment of the small intestine, and 64.4% of the ribavirin was absorbed before it reached the ileum. In addition, it was revealed that ribavirin was metabolized more extensively in the intestine than in the liver. Our method may be effective in quantitatively assessing Fa and Fg in vivo, which can help in the formulation design and prediction of drug-drug interactions.