Formed and preformed metabolites: facts and comparisons

Abstract

The administration of metabolites arising from new drug entities is often employed in drug discovery to investigate their associated toxicity. It is expected that administration of metabolites can predict the exposure of metabolites originating from the administration of precursor drug. Whether exact and meaningful information can be obtained from this has been a topic of debate. This communication summarizes observations and theoretical relationships based on physiological modelling for the liver, kidney and intestine, three major eliminating organs/tissues. Theoretical solutions based on physiological modelling of organs were solved, and the results suggest that deviations are expected. Here, examples of metabolite kinetics observed mostly in perfused organs that did not match predictions are provided. For the liver, discrepancies in fate between formed and preformed metabolites may be explained by the heterogeneity of enzymes, the presence of membrane barriers and whether transporters are involved. For the kidney, differences have been attributed to glomerular filtration of the preformed but not the formed metabolite. For the intestine, the complexity of segregated flows to the enterocyte and serosal layers and differences in metabolism due to the route of administration are addressed. Administration of the metabolite may or may not directly reflect the toxicity associated with drug use. However, kinetic data on the preformed metabolite will be extremely useful to develop a sound model for modelling and simulations; in-vitro evidence on metabolite handling at the target organ is also paramount. Subsequent modelling and simulation of metabolite data arising from a combined model based on both drug and preformed metabolite data are needed to improve predictions on the behaviours of formed metabolites.

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

“…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). Upon incorporation of interconversion between the precursor and metabolite and alternate metabolic pathways in present PBPK model, we provided analytical solutions and showed that, in the presence of futile cycling, the eliminatory parameters of the metabolite would affect the disposition of the precursor (Table 2).…”

“…Ordinarily, metabolite parameters would not have an impact on parent drug processing (Pang et al, 2008). However, metabolite and drug parameters do affect the net metabolism, via the coefficient, ef m Ј, when futile cycling exists (Table 2).…”

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

“…It has been recognized that, generally, compartmental modeling is unable to quantitatively address the multiplicity of metabolite formation organs and does not account for sequential metabolism/excretion nor permeability barriers of formed metabolites (Pang et al, 2008;Pang, 2009). In contrast, physiologically based pharmacokinetic (PBPK) models address events of sequential elimination and include transmembrane barriers Pang, 1986, 1993;Pang, 2003;Pang et al, 2009;Chow and Pang, 2013) and transporters (Sun et al, 2006.…”

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).…”

“…These three intestinal models are viewed as competent to describe the immediate removal of the formed metabolite by excretion or sequential metabolism within the intestine and/or further processing by liver, for drugs and metabolites exhibiting varying permeability properties (Cong et al, 2000;Yang et al, 2006Yang et al, , 2007Gertz et al, 2010;Sun and Pang, 2010). The models are more prepared to supply mechanistic insight into the pharmacokinetics of drugs and their metabolites and allow inclusion of transporters into different organ components (apical or basolateral membranes) to discriminate between the permeability properties of the drug and its formed metabolite in permitting or delimiting influx and efflux in drug and metabolite processing (Pang et al, 2008;Darwich et al, 2010;Galetin et al, 2010;Gertz et al, 2010;Rowland Yeo et al, 2010;Chow and Pang, 2013). By virtue of inclusion of transport and eliminatory events, these physiologically based models are able to more accurately describe the net appearance of the formed metabolite into the systemic circulation, because metabolite levels can be drastically reduced as a result of sequential metabolism (Pang and Gillette, 1979).…”