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Interplay of drug metabolism and transport: a real phenomenon or an artifact of the site of measurement?

ABSTRACT: The interdependence of both transport and metabolism on the disposition of drugs has recently gained heightened attention in the literature, and has been termed the "interplay of transport and metabolism". Such "interplay" is observed when inhibition of biliary clearance of a drug results in an "apparent" increase in the metabolic clearance of the drug or vice versa. In this manuscript, we derived and explored through simulations a physiological-based pharmacokinetic model that integrates both transport and metabolism and explains the "apparent" dependence of hepatic clearance on both these processes. In addition, we show that the phenomenon of hepatic "transport-metabolism interplay" is a result of using the plasma concentration as a point of reference when calculating metabolic or biliary clearance, and this interplay is maximal when the drug is actively transported into the hepatocytes (i.e., hepatocyte sinusoidal influx clearance is greater than the sinusoidal efflux clearance). When the hepatic drug concentration is used as a reference point to calculate metabolic or biliary clearance, this interplay ceases to exist. A mechanistic understanding of this interplay phenomenon can be used to explain the somewhat paradoxical results that may be observed in drug-drug interaction studies when a drug is cleared by both metabolism and biliary excretion. That is, when one of these two pathways is inhibited, the other pathway appears to be induced or activated. This interplay results in an increase in hepatic drug concentrations and therefore has implications for the hepatic efficacy and toxicity of a drug.

SUBMITTER: Endres CJ

PROVIDER: S-EPMC2801584 | biostudies-literature | 2009 Nov-Dec

REPOSITORIES: biostudies-literature

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Interplay of drug metabolism and transport: a real phenomenon or an artifact of the site of measurement?

Endres Christopher J CJ Endres Michael G MG Unadkat Jashvant D JD

Molecular pharmaceutics 20091101 6

The interdependence of both transport and metabolism on the disposition of drugs has recently gained heightened attention in the literature, and has been termed the "interplay of transport and metabolism". Such "interplay" is observed when inhibition of biliary clearance of a drug results in an "apparent" increase in the metabolic clearance of the drug or vice versa. In this manuscript, we derived and explored through simulations a physiological-based pharmacokinetic model that integrates both t ...[more]

PMID: 19886641

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Project description:The layer-by-layer film deposition is a suitable strategy for the design and functionalization of drug carriers with superior performance, which still lacks information describing the influence of assembly conditions on the mechanisms governing the drug release process. Herein, traditional poly(acrylic acid)/poly(allylamine) polyelectrolyte multilayers (PEM) were explored as a platform to study the influence of the assembly conditions such as pH, drug loading method, and capping layer deposition on the mechanisms that control the release of calcein, the chosen model drug, from PEM. Films with 20-40 bilayers were assembled at pH 4.5 or 8.8, and the drug loading process was carried out during- or post-film assembly. Release data were fitted to three release models, namely, Higuchi, Ritger-Peppas, and Berens-Hopfenberg, to investigate the mechanism governing the drug transport, such as the apparent diffusion and the relaxation time. The postassembly drug loading method leads to a higher drug loading capacity than the during-assembly method, attributed to the washing out of calcein during film assembly steps in the latter method. Higuchi's and Ritger-Peppas' model analyses indicate that the release kinetic constant increased with the number of bilayers for the postassembly method. The opposite trend is observed for the during-assembly method. The Berens-Hopfenberg release model enabled the decoupling of each drug transport mechanism's contribution, indicating the increase of the diffusion contribution with the number of bilayers for the postassembly method at pH 4.5 and the increase of the polymer relaxation contribution for the during-assembly method at pH 8.8. Deborah's number, which represents the ratio of the polymer relaxation time to the diffusion time, follows the trends observed for the relaxation contribution for the conditions investigated. The deposition of the capping phospholipid layer over the payload also favored the polymer relaxation contribution in the drug release, featuring new strategies to investigate the drug release in PEM.

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Dataset Information

Interplay of drug metabolism and transport: a real phenomenon or an artifact of the site of measurement?

Publications

Interplay of drug metabolism and transport: a real phenomenon or an artifact of the site of measurement?

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