PBPK Modeling of Intestinal and Liver Enzymes and Transporters in Drug Absorption and Sequential Metabolism

Abstract

Experimental strategies have long been applied for in vitro or in vivo evaluation of the effect of transporters and/or enzymes on the bioavailability. However, the lack of specific inhibitors or inducers of transporters and enzymes and the multiplicity of nuclear receptors in gene regulation and cross talk have led to compromised assessment of these effects in vivo. These and other causes have resulted in confusion and controversy in transporter-enzyme interplay. In this review, physiologically-based pharmacokinetic (PBPK) intestinal and liver models are utilized to predict the contributions of enzymes and transporters on intestinal availability (F(I)) and hepatic availability (F(H)), with the aim to fully understand the impact of these variables on bioavailability (F(sys)) in vivo. We emphasize the often overlooked impact of influx and efflux clearances, and apply the PBPK models and their solutions to examine individual organ clearances of the intestine and the liver. In order to accurately predict oral bioavailability, these organ models are incorporated into the whole body PBPK model, and additional complicated scenarios such as segmental differences and zonal heterogeneity of transporters and enzymes in the intestine and liver and segregated blood flow patterns of the intestine are further discussed. The sequential metabolism of a drug to form primary and secondary metabolites in the first-pass organs is considered in PBPK modeling, revealing that the segregated flow model (SFM) of the intestine is more appropriate than the traditional PBPK intestinal model (TM). Examples are included to highlight the potential application of these PBPK models on the quantitative prediction of bioavailability.

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

“…Route-dependent metabolism by the intestine is repeatedly being observed (namely, a higher extent of intestinal metabolism exists when a drug is given orally versus the lower extent or virtual absence of intestine metabolism when the drug is given systemically) (Cong et al, 2000;Doherty and Pang, 2000;Fan et al, 2010). This was observed for erythromycin (Lown et al, 1995) and midazolam (Paine et al, 1996) in humans and for enalapril hydrolysis (Pang et al, 1985) and morphine glucuronidation in the rat intestine .…”

“…This was observed for erythromycin (Lown et al, 1995) and midazolam (Paine et al, 1996) in humans and for enalapril hydrolysis (Pang et al, 1985) and morphine glucuronidation in the rat intestine . The lesser extent of intestinal metabolism for systemically delivered drugs is explained by the pattern that a fraction and not the entire intestinal blood flow perfuses and recruits enzymes/excretory transporters in the enterocyte region, with the majority of flow perfusing the inactive, serosal region (Cong et al, 2000;Fan et al, 2010). These observations led to the development of the segregated flow model (SFM), describing that only a partial intestinal flow (5%-30%) reaches the enterocyte region to explain the higher oral versus intravenous intestinal metabolism.…”

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGutModel

“…Compartmental models are no longer adequate to address effects of permeability barriers Pang, 1986, 1987), intestinal and liver transporters and enzymes (Suzuki and Sugiyama, 2000a,b), and sequential metabolism within the intestine and liver (Pang and Gillette, 1979;Sun and Pang, 2010) during oral drug absorption (for reviews, see Pang, 2003;Pang et al, 2008;Fan et al, 2010;Pang and Durk, 2010;Chow and Pang, 2013). These aspects are especially pertinent when intestinal metabolic activity is substantial relative to that in the liver, and when different extents of induction/inhibition of intestinal and hepatic enzymes or transporters are the result of treatment with the culprit compound, which usually shows a higher induction/inhibition effect with oral administration (Fromm et al, 1996;Paine et al, 1996;Thummel et al, 1996;Eeckhoudt et al, 2002;Mouly et al, 2002;Fang and Zhang, 2010;Liu et al, 2010;Lledó-García et al, 2011;Zhu et al, 2011).…”

“Target-Site” Drug Metabolism and Transport

“…This interplay has been evaluated at the level of common regulatory pathways for XMEs and transporters, and in regard to the pharmacokinetics of compounds that are substrates for both XMEs and transporters (Nies et al, 2008;Pang et al, 2009;Zhang et al, 2009;Fan et al, 2010). XMEs as well as drug transporters share common regulatory pathways; for example, pregnane X receptor, constitutive androstane receptor, AhR/ARNT, and Nrf2-Keap mediated regulation of protein expression.…”