Physiological Modeling to Understand the Impact of Enzymes and Transporters on Drug and Metabolite Data and Bioavailability Estimates

Abstract

The AUC ratio of the formed metabolite after oral and intravenous drug dosing differed from that for drug and would not provide F (sys). However, the AUC ratio of the formed metabolite for oral and intravenous drug dosing furnished the estimate of F (abs) when intestine or liver was the only drug metabolic organ.

Interplay of Phase II Enzymes and Transporters in Futile Cycling: Influence of Multidrug Resistance-Associated Protein 2-Mediated Excretion of Estradiol 17β-d-Glucuronide and Its 3-Sulfate Metabolite on Net Sulfation in Perfused TR−and Wistar Rat Liver Preparations

“…With intentions of defining the role of membrane transporters and enzymes, we had previously used the PBPK model that describes transporter-and enzyme-mediated processes, such as basolateral influx, efflux, canalicular secretion, and metabolism and allows one to appraise the significance of rate-limited pathways and transporterenzyme interplay (de Lannoy et al, 1993;Liu and Pang, 2005;Shitara et al, 2006;Sun et al, 2006;Sun and Pang, 2010). However, most of the focus was on precursor-metabolite pairs that undergo irreversible metabolism, and AUC R {mi,P} of the formed metabolite was found to be modulated by eliminatory parameters of the precursor and not vice versa (de Lannoy et al, 1993;Pang et al, 2008) (Tables 1 and 2 when CL int,met Mi3 D {mi} ϭ 0).…”

“…For example, the sulfated metabolite formed via sulfotransferases (SULTs) in the cytosol may access the arylsulfatases in the endoplasmic reticulum to become desulfated to re-form the parent drug (Ratna et al, 1993;Kauffman et al, 1998). Acinar heterogeneity of the SULTs further complicates the scenario (Xu et al, 1993;Tan et al, 2001).A well-stirred liver model with membrane barriers has been shown to be useful to relate the physiological and biochemical factors to hepatic drug and metabolite processing (Sirianni and Pang, 1997;Liu and Pang, 2005;Sun and Pang, 2010). In brief, transporter or enzyme activity is denoted by the intrinsic clearance or the ratio of V max , the maximum rate of the enzyme or transporter-mediated process, and K m , the Michaelis-Menten constant, under linear conditions.…”

“…A well-stirred liver model with membrane barriers has been shown to be useful to relate the physiological and biochemical factors to hepatic drug and metabolite processing (Sirianni and Pang, 1997;Liu and Pang, 2005;Sun and Pang, 2010). In brief, transporter or enzyme activity is denoted by the intrinsic clearance or the ratio of V max , the maximum rate of the enzyme or transporter-mediated process, and K m , the Michaelis-Menten constant, under linear conditions.…”

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).…”

Physiologically based pharmacokinetic (PBPK) modelling tools: how to fit with our needs?

“…This has seen increasingly widespread popularity among certain groups, notably that of Sugiyama, whose publications cite the use of SAAM for their reported PBPK models of hepatic uptake and biliary clearance of pravastatin [42], concentration-dependent intestinal permeability of P-gp substrates [43], and others. The group of Pang have also been instrumental in contributing new insights into physiological modelling of transporter-mediated processes and metabolite kinetic, again using open modelling software to write and solve their models of intestinal and zonal hepatic transport and metabolism, which when incorporated into WB-PBPK models are able to account for phenomena such as routedependent metabolism which were not explainable when using simpler, more standard PBPK models [44]. Within the pharmaceutical industry, several publications by the R & D DMPK group of AstraZeneca have also reported the use of software such as WinNonlin and Berkley Madonna in the construction of their hepatocyte PBPK models [29,45,46].…”