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      Lovastatin and Simvastatin - Inhibitors of HMG CoA Reductase and Cholesterol Biosynthesis

      Cardiology

      S. Karger AG

      Lovastatin, Simvastatin, Prodrug, Liver, Cholesterol synthesis

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          Abstract

          The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is a key rate-controlling step early in the cholesterol biosynthetic pathway that catalyzes the conversion of HMG CoA to mevalonic acid. Since this enzyme plays a significant role in regulating cholesterol synthesis, it is a rational target for pharmacologic intervention. The first potent, specific inhibitor of HMG CoA was mevastatin (compactin, ML-236B) which was discovered in 1976 by Endo et al. [J Antibiot 1976;29:1346-1348]. Subsequently, lovastatin, a novel, more active fungal metabolite was isolated from a strain of Aspergillus terreus.Lovastatin, the first of this class of agents to be approved for clinical use, was chemically modified to form simvastatin. Simvastatin is superior to lovastatin in intrinsic inhibitory potency. Both are inactive lactone prodrugs that must be converted to their respective dihy-droxy open-acid forms to elicit inhibitory activity. Pharmacologic characterization of lovastatin and simvastatin has demonstrated that these potent inhibitors of HMG CoA reductase specifically inhibit cholesterol synthesis in animal cells, as well as in vivo after oral administration of the agents. Oral administration of either lovastatin or simvastatin to dogs in the presence or absence of the bile acid sequestrant cholestyramine results in a marked, sustained lowering of plasma cholesterol. Associated with the cholesterol lowering is a decrease in urinary and plasma levels of mevalonic acid, the end product of the HMG CoA reductase reaction. The target organ for inhibitors of HMG CoA reductase is the liver, the primary site of cholesterol biosynthesis. Both lovastatin and simvastatin are preferentially extracted by this organ. In studies in the rat in which direct measurements of drug levels have been carried out, much more inhibitory activity derived from the prodrugs lovastatin and simvastatin is found in the liver than in spleen, testes, and kidney. This is reflected in a much greater in vivo inhibition of cholesterol synthesis in the liver by these agents than in the periphery. In summary, the HMG CoA reductase inhibitors lovastatin and simvastatin are potent inhibitors of mevalonic acid synthesis in vitro and in vivo. They are preferentially concentrated in the liver, the target organ. This results in inhibition of cholesterol synthesis and a concomitant decrease in plasma low-density lipoprotein cholesterol in experimental animals and humans.

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          Author and article information

          Journal
          CRD
          Cardiology
          10.1159/issn.0008-6312
          Cardiology
          S. Karger AG
          978-3-8055-5278-3
          978-3-318-00092-4
          0008-6312
          1421-9751
          1990
          1990
          12 November 2008
          : 77
          : Suppl 4
          : 14-21
          Affiliations
          Merck Sharp & Dohme Research Laboratories, Rahway, N.J., USA
          Article
          174688 Cardiology 1990;77:14–21
          10.1159/000174688
          2073667
          © 1990 S. Karger AG, Basel

          Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

          Page count
          Pages: 8
          Categories
          HMG CoA Reductase Inhibitors: New Horizons in the Management of Hypercholesterolemia

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