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Effects of Hepatic Drug Metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

Ennulat, Daniela and Walker, Dana and Clemo, Frances and Magidslav, Michal and Ledieu, David and Graham, Mark and Botts, Suzanne and Boone, Laura (2010) Effects of Hepatic Drug Metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man. Toxicologic Pathology.

Abstract

Hepatic drug metabolizing enzyme (DME) induction is an adaptive response associated with changes in preclinical species that can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of drug metabolizing enzymes. Effects of DME induction on clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established. In this component of a multipart review of the comparative pathology of xenobiotically-mediated induction of hepatic metabolizing enzymes, pertinent data from retrospective and prospective preclinical and clinical studies are reviewed. Particular attention is given to studies with confirmation of DME induction and concurrent evaluation of liver and/or serum hepatobiliary marker enzyme activities and histopathology. These results collectively indicate that in the rat, when histologic findings are limited to hepatocellular hypertrophy, DME induction is not expected to be associated with consistent or substantive changes in serum or plasma activity of hepatobiliary marker enzymes such as ALT, ALP and GGT. In dog and monkey, published studies also do not demonstrate a consistent relationship across DME inducing agents and changes in these clinical pathology parameters. However, increased liver ALP or GGT activity in dogs treated with phenobarbital or corticosteroids suggest that direct or indirect induction of select hepatobiliary injury markers can occur both in the absence of liver injury and independently of induction of DME activity. While correlations between tissue and serum levels of these hepatobiliary markers are limited and inconsistent, increases in serum/plasma activities that are substantial or involve changes in other markers generally reflect hepatobiliary insult rather than DME induction. Extrahepatic effects including disruption of the hypothalamic-pituitary-thyroid axis can also occur as a direct outcome of hepatic DME induction in humans and animals. Importantly, hepatic DME induction and associated changes in preclinical species are not necessarily predictive of the occurrence, magnitude or enzyme induction profile in humans.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2428

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