Scientific Publications by FDA Staff

Drug Metab Dispos 2016 Jul;44(7):1123-38

Metabolite kinetics: the segregated-flow model (SFM) for intestinal and whole body PBPK modeling to describe intestinal and hepatic glucuronidation of morphine in rats in vivo.

Yang QJ, Fan J, Chen S, Liu L, Sun H, Pang KS

We used the intestinal segregated flow (SFM) vs. the traditional (TM) model, nested within physiologically-based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3beta-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in ratsin vivo The SFM model describes a partial (5-30%) intestinal blood flow perfusing the transporter- and enzyme-rich enterocyte region whereas the TM describes 100% flow perfusing the intestine as a whole. For the SFM, drugs entering from the circulation are expected to be metabolized to lesser extents by the intestine due to the segregated flow than for the TM, reflecting the phenomenon of shunting and route-dependent intestinal metabolism. The poor permeability of MG in crossing the liver or intestinal basolateral membranes mandates that most of MG that is excreted into bile is hepatically formed, whereas MG that is excreted into urine originates from both intestinal and hepatic metabolism, since MG is effluxed back to blood. The ratio of MG amounts in urine/bile (AUCMG urine/AUCMG bile) for intraduodenal/intravenous is expected to exceed unity for the SFM but approximate unity for the TM. Compartmental analysis of M and MG data, without consideration of the permeability of MG and where MG is formed, suggests the ratio to be 1, and failed to describe the kinetics of MG. The observed intraduodenal/intravenous ratio of AUCMG urine,4h/AUCMG bile,4h(2.55 at 4 h) was better predicted by the SFM (2.59 at 4 h) and not the TM (1.0), supporting the view that SFM is superior for the description of intestinal-liver metabolism of morphine to MG.