Physiologically ‐Based Pharmacokinetic Modeling Revealed Minimal Codeine Intestinal Metabolism in First‐Pass Removal in Rats

We presently applied the same PBPK modeling approaches to examine the contributions of the intestine and liver on first‐pass metabolism of the precursor, codeine (C, 3‐methylmorphine) in the rat. Unexpectedly, profiles of C, M, and MG 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 M (from C) for the liver was much higher, being 9‐ to 13‐fold that of the intestine. Simulations, based on absence of intestinal formation of M, 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 C metabolism. Because of little or no contribution by the intestine to the metabolism of C, both the TM‐ and SFM‐PBPK models are equally consistent with the data.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research