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

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). 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. 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.