Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo.
We used the intestinal segregated flow model (SFM) versus the traditional model (TM), nested within physiologically based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3β-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in rats in 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, reflecting the phenomenon of shunting and route-dependent intestinal metabolism. The poor permeability of MG 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 intestine and liver metabolism, since MG is effluxed back to blood. The ratio of MG amounts in urine/bile [Formula: see text] for intraduodenal/intravenous dosing is expected to exceed unity for the SFM but approximates unity for the TM. Compartmental analysis of morphine 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 [Formula: see text] (2.55 at 4 hours) was better predicted by the SFM-PBPK (2.59 at 4 hours) and not the TM-PBPK (1.0), supporting the view that the SFM is superior for the description of intestinal-liver metabolism of morphine to MG. The SFM-PBPK model predicts an appreciable contribution of the intestine to first pass M metabolism.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Qi Joy
QJ
Yang
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Jianghong
J
Fan
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Shu
S
Chen
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Lutan
L
Liu
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Huadong
H
Sun
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada ks.pang@utoronto.ca.
K Sandy
KS
Pang
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D002463:Cell Membrane Permeability; D004386:Duodenum / Q000098:blood supply* / Q000378:metabolism*; D065669:Hepatobiliary Elimination; D008658:Inactivation, Metabolic; D008099:Liver / Q000098:blood supply* / Q000378:metabolism*; D008102:Liver Circulation; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D009022:Morphine Derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D065667:Renal Elimination; D013152:Splanchnic Circulation
D009022:Morphine Derivatives; D009020:Morphine; C018108:morphine-3-glucuronide