1
`
`EX 1019
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`CHURCHILL LIVINGSTONE
`Medical Division of Longman Group UK
`Limited
`
`ACKNOWLEDGEMENTS
`
`Publishing manager: Timothy Horne
`Project coordinator." Julia Merrick
`Design: Design Resource Unit
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`Computer Services." Janet Mundy and User Friendly Computer Services
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`Ea't'tort'aI Assistant.‘ Patricia Aubertel
`Sal'espr0m01i0r1.' Hilary Brown
`
`The publishers also gratefully acknowledge the help given by
`many others, particularly the coordinators in the early stages
`of the project: Susan Faulding and Helen Orpe.
`
`Distributed in the United States of America by
`Churchill Livingstone Inc., 1560 Broadway,
`New York, N.Y. 10036, and by associated
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`throughout the world.
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`© Longman Group UK Limited 199!
`
`All rights reserved. No part of this publication
`may be reproduced, stored in a retrieval system,
`or transmitted in any form or by any means,
`electronic, mechanical, photocopying, recording
`or otherwise, without either the prior written
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`EH1 3AF), or a licence permitting restricted
`copying in the United Kingdom issued by the
`Copyright Licensing Agency Ltd, 90 Tottenham
`Court Road, London, WClE7DP.
`
`l—3
`
`First published 1991
`
`ISBN D-'-l‘-IEI-E|EE»'-ll:-X
`
`British Library Cataloguing in Publication Data
`CIP catalogue record for this book is available
`from the British Library.
`
`Library of Congress-in-Publication Data
`Therapeutic drugs/‘edited by Sir Colin Dollery; editorial board,
`Alan R. Boobis
`[et al.].
`p. cm.
`Includes bibliographical references and indexes.
`1. Drugs—Handbooks, manuals, etc. 2. Pharmacology—Handbooks,
`manuals, etc. I. Dollery, Colin T.
`[DNLM: 1. Drug Therapy—handbooks. 2. Drugs—-ljiandbooks. QV 39
`T398]
`5‘
`RM30I.l2.T44 I991
`6l5.5‘El—dc20
`DNLM/DLC
`for Library of Congress ‘
`
`D__;_,,,,,; .....u i........4 :.. r:....... n..:+..:.. I...
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`2
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`

`
`Spironolactone
`
`Spironolactone is probably the most important steroidal lactone in
`clinical use;
`it acts as a diuretic and antihypertensive agent by
`antagonizing the sodium—retaining effects of aldosterone, and also in
`part by inhibiting the adrenocortical biosynthesis of aldosterone.
`
`Chemistry
`Spironolactone (Aidactone, Dialensec, Spiroctan, Spirolone)
`C2-1H:!2O4s
`7-oi-Acetyl-thio-3-oxo-i71~pregn—4—e-ne—2i—17fl—carbo|actone acid—y-
`lactone
`
`Molecular weight
`pKa
`Solubility
`in alcohol
`in water
`Octanol/water partition coefficient
`
`416.1
`not relevant
`
`in 80
`1
`insoluble
`—
`
`Spironolactone is a white to light tan powder with a slightly bitter
`taste and is usually odourless or has a slight odour of thioacetic acid.
`It is prepared by chemical synthesis.
`Spironolactone is also available in oral combination with fruse—
`Inide (Lasilactone=frusernide 20 mg and spironolactone 50 mg) and
`with hydroflumethiazide (Aldactide 25=hydrofiumethiazide 25mg
`and spironolactone 25 mg).
`
`Pharmacology
`The antimineralocorticoid properties of the spirolactones were first
`recognized more than 30 years ago.1 Spironolactone is a competitive
`inhibitor of the binding of aldosterone to its receptor.
`Its most
`important site of action is the distal portion of renal tubules where it
`combines with soluble cytoplasmic aldosterone receptors to form
`Complexes which are inactive and which do not bind to nticlear-
`acceptor sites, thus preventing a chain of biochemical events leading
`to the synthesis of physiologically active proteins.” Thus it pro-
`motes a diuresis and acts as an antihypertensive agent. Administra-
`tion of spironolactone is associated with reversal of the electrolytic
`Changes attributed to aldosterone and with a dose-dependent increase
`in plasma renin activity in rats.‘
`A separate but less important efiect is direct inhibition of adrenal
`Synthesis of aldosterone.5
`
`Toxicology
`The acute toxicity of spironolactone is low in rats. mice and rabbits.
`50 that there is a high potential therapeutic ratio.
`During chronic testing histological changes were noted in rat liver,
`thyroid gland and male genitalia. There were also changes in monkey
`testes and male mammary glands.
`In a 78-week study in rats. a
`number of malignant tumours occurred. mainly aficcting skin and
`
`with a control group it was not clear that the incidence of tiiniours
`was greater than would be expected in any ageing rat population,
`Thus. whether spironolactone predisposes to tumour
`formation
`remains an unresolved question.°
`
`Clinical pharmacology
`Spironolactone is a competitive inhibitor of aldosterone through
`binding at receptor sites, the most important of which lie in the late
`distal renal
`tubules and the renal collecting system. Thus urinary
`sodium and water loss and retention ofpotassium and hydrogen result
`and the clinical efiects are a diuresis and lowering of blood pressure.7
`Spironolactone also inhibits adrenocortical aldosterone biosyiithe-
`sis in patients with primary hyperaldosteronisin. of which ‘spirono-
`lactone bodies‘
`identified in the adrenal
`tumour cells of treated
`patients are thought to be a morphological expression.3 Theoreti-
`cally. such a mechanism could enhance diuretic activity but
`its
`therapeutic importance is uncertain.
`Spironolactone is primarily useful as a diuretic in patients with
`hyperaldosteronism. Thus it is eifective in patients with ascites due to
`liver failure, and in patients with resistant heart failure (i.e. where
`other diuretics have failed). It is less useful as a first—line diuretic. its
`antiliypertensive effects are relatively modest in essential hyperten-
`sion but it is of value in the treatment ofhypertension clue to primary
`hyperaldosteronism where other definitive treatments (e.g. surgery)
`are not feasible.
`Single-dose studies in normal volunteers in the range 50—800 mg
`produced a dose-dependent reversal of aldosterone-induced sodium
`retention and/or decrease in the plasma Na,lK ratiO.9 In essential
`hypertension no difference in antihypertensive eflect was found
`between daily doses of 100, 200 or 400 mg” and a maximum dose of
`75-100 mg per day has been recommended.“ However. there was a
`close relationship with plasma sodium. potassium and weight.” By
`comparison. spironolactone in doses of up to 400 mg per day may be
`necessary in the treatment of primary hyperaldosteronisru.7'” Be-
`cause of the prolonged duration of activity of its metabolites,
`spironolactone may be administered in a single daily dose.
`Spironolactone causes a number of electrolyte changes. notably a
`reduction in plasma sodium and bicarbonate, together with dose-
`dependent elevations in plasma renin, potassium and Creatinine.
`Fasting blood sugar. cholesterol and triglycerides are not significantly
`affected.“'13
`Spironolactone was thought to increase calcium excretion through
`a direct effect on tubular transport, but this was later refuted.“
`
`Pharmacokinetics
`
`In the past spironolactone has been assayed using a spectrophotoliu-
`orimetric method” but now a HPLC assay is in more common use
`which has a sensitivity”"” of5 ttgi”. However, because the drug is
`extensively metabolized to canrenone and other metabolites which
`are also competitive antagonists ol‘ aldosterone. pharmacokinetic
`studies focus on the metabolic pathways.
`Oral absorption of spironolactone is variable because of its low
`aqueous solubility. In rhesus monkeys almost complete absorption of
`the drug was obtained f1'om an aqueous ethanolic solution. and in
`man, absorption is enhanced by micronization of the drug in the
`tablet.1B'19 There is improved absorption if the drug is taken after
`food, probably because by delaying gastric emptying, food promotes
`disintegration of the tablet and improves dissolution of the drug.
`Furthermore. bile acids secreted in response to the meal may
`dissolve spironolactone. which is very lipophilicw The peak plasma
`concentration was observed at
`1 hour in normal volunteers after a
`standardized meal. Systemic bioavailability has been estimated at
`60-70% and the plasma halflife is l.3 10.3 (SD) hours. The drug can
`still be detected up to 8 hours after ingestion but it
`is extensively
`metabolized so that the free drug is not detected in t1rine_21‘Z3
`Spironolactone is 98% protein bound but its volume of distribu-
`tion is unknown.“ The extent oftissue accumulation of the drug and
`its ability to cross the blood—brain barrier are not known.
`In
`lactating women taking spironolactone, levels of canreiione in milk
`were low and it was estimated that
`the maximum quantity of
`canrcnone ingested daily by the human infant via milk was 0.2% of
`the maternal daily dose of spironolactone.”
`
`3