title: Physiologically based pharmacokinetic modeling revealed minimal codeine intestinal metabolism in first-pass removal in rats.
abstract: The physiologically based model with segregated flow to the intestine (SFM-PBPK; partial, lower flow to enterocyte region vs. greater flow to serosal region) was found to describe the first-pass glucuronidation of morphine (M) to morphine-3β-glucuronide (MG) in rats after intraduodenal (i.d.) and intravenous (i.v.) administration better than the traditional model (TM), for which a single intestinal flow perfused the whole of the intestinal tissue. The segregated flow model (SFM) described a disproportionately greater extent of intestinal morphine glucuronidation for i.d. vs. i.v. administration. The present study applied the same PBPK modeling approaches to examine the contributions of the intestine and liver on the first-pass metabolism of the precursor, codeine (C, 3-methylmorphine) in the rat. Unexpectedly, the profiles of codeine, morphine and morphine-3β-glucuronide in whole blood, bile and urine, assayed by LCMS, were equally well described by both the TM-PBPK and SFM-PBPK. The fitted parameters for the models were similar, and the net formation intrinsic clearance of morphine (from codeine) for the liver was much higher, being 9- to 13-fold that of the intestine. Simulations, based on the absence of intestinal formation of morphine, correlated well with observations. The lack of discrimination of SFM and TM with the codeine data did not invalidate the SFM-PBPK model but rather suggests that the liver is the only major organ for codeine metabolism. Because of little or no contribution by the intestine to the metabolism of codeine, both the TM- and SFM-PBPK models are equally consistent with the data. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Keumhan
authors.initials: K
authors.lastname: Noh
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.|Apotex Inc., 150 Signet Drive, Toronto, Ontario, M9L 1T9, Canada.
authors.forename: Shu
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Qi J
authors.initials: QJ
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
mesh_terms: D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism; D003061:Codeine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000097:blood / Q000652:urine; D009022:Morphine Derivatives / Q000097:blood / Q000652:urine; D017207:Rats, Sprague-Dawley
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D009020:Morphine; C018108:morphine-3-glucuronide; D003061:Codeine
keywords: codeine; first-pass intestinal vs. liver metabolism; glucuronidation; morphine; physiologically based pharmacokinetic model; segregated flow model; traditional model