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Active and Reactive Metabolites Formed During Hepatic First-Pass: Simulations Featuring Their Contribution to the Overall Effect in Altered Liver Clearance and Drug-Drug Interactions

Ahmed Abdelaziz, Helmholtz Zentrum München, Germany
Hilde Spahn-Langguth, University of Graz, Austria

Phase-I- and – occasionally – also phase-II metabolites may contribute to the overall effect of a drug, they might as well induce toxicity. For example, the chemical reactivity of these acyl glucuronides has been linked with the toxic properties of some drugs that contain a carboxylic acid moiety. This is not always apparent or revealed, since total concentrations of metabolites may be low in relation to parent drug concentrations. In the case of carvedilol, using a comparison of HPLC and beta 1-specific radioligand-receptor-binding assay (RRA), it was possible to demonstrate that regarding beta-adrenoceptor blockade the effect appears directly linked to the serum compartment, which indicates instantaneous equilibrium between the blood compartment and the biophase, and that oxidative metabolites significantly contribute to the effect, particularly after oral administration. This drug serves as model compound in different approaches for evaluating the role of formation of active metabolites during first-pass when hepatic clearance varies. 

The computational approach is one of the modern and fastest developing prescreening techniques in pharmacokinetics, ADME (absorption, distribution, metabolism, excretion) evaluation, drug discovery, and toxicity. Validation of the respective procedures may be performed retrospectively on the basis of available data. Moreover, we are trying to use the predictive approach to identify and characterize potentially active or reactive metabolites, which need to be accounted for when they contribute to the overall effect pattern to a considerable extent. The current study mainly aims at the characterization of the kinetic properties of carvedilol metabolites, for which a significant contribution to an effect segment was detected in our previous studies.

For carvedilol, the hepatic extraction ratio is considerable, and the oral availability (calculated assuming complete absorption and no intestinal elimination) amounts to 25% to 35 % for parent drug due to extensive first pass metabolism. And in spite of their low serum levels, the contribution of the metabolites must not be neglected, especially for oral dosing. Elimination of parent drug was found to be rate-limiting, i.e., the kinetics of the metabolites is formation-rate limited, at least in healthy volunteers. The AM-FP model was most suitable, since parent drug and metabolites appear to enter the systemic circulation simultaneously. The new compartmental model is applicable for PK/PD simulation studies including situations, where hepatic clearance is affected. It was used to simulate the contribution of active metabolites formed during first-pass to the overall effect, also under conditions of impaired liver function leading to reduced metabolic clearance and in case of drug-drug interactions that are hypothesized to induce absorption.

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