Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery

Abstract

1. In this study an advanced multisampling site pig model, with simultaneous venous blood sampling pre- and post liver, was applied to quantify the role of the intestine in relation to the liver in first-pass glucuronidation of raloxifene in vivo. The pharmacokinetic of raloxifene (a BCS/BDDCS class II compound) in humans is characterized by extensive metabolism (>90%) and the major metabolite is the 4′-β-glucuronide (R-4-G).

2. Following intra-jejunal (i.j.) single dose administration in pigs raloxifene was metabolized in the gut (E_G) during first-pass to more than 70% and a high concentration (AUC_{0–6 h} ratio R-4-G/raloxifene >100) of R-4-G was reached in the portal vein. The hepatic extraction (E_H) of raloxifene was ~50% and as in humans the bioavailability become low (~7%) in pigs. Interestingly the E_H of raloxifene and R-4-G was time-dependent after i.j. administration.

3. It is clear that the gut was the dominating organ in first-pass extraction of raloxifene in vivo in pigs. The quantification in this study support earlier human data and emphasize that intestinal glucuronidation should be considered early in the pharmaceutical development.

Keywords:

• Raloxifene
• glucuronidation
• pigs
• intestinal metabolism
• first-pass metabolism