Journal of Dialysis
`
`ISSN: 0362-8558 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/irnf17
`
`Drug Metabolism and Active Drug Metabolites in
`Renal Failure
`
`Marcus M. Reidenberg & Dennis E. Drayer
`
`To cite this article: Marcus M. Reidenberg & Dennis E. Drayer (1977) Drug Metabolism
`and Active Drug Metabolites in Renal Failure, Journal of Dialysis, 1:4, 313-318, DOI:
`10.3109/08860227709038422
`
`To link to this article: http://dx.doi.org/10.3109/08860227709038422
`
`Published online: 07 Jul 2009.
`
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`Download by: [Margaret Smith]
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`Date: 07 March 2016, At: 08:27
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`Boehringer Ex. 2023
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`JOURNAL OF DIALYSIS, 1(4), 313-318 (1977)
`
`EDITORIAL
`
`DRUG METABOLISM AND ACTIVE DRUG METABOLITES
`IN RENAL FAILURE
`
`A r e l a t i v e l y small number of drugs are e l i m i n a t e d
`from t h e body by r e n a l e x c r e t i o n of t h e drug i t s e l f .
`Some of these drugs are:
`c o l i s t i n
`
`p e n i c i l l i n
`
`procainamide
`d i goxin
`aminoglucoside a n t i b i o t i c s
`
`c y c l o s e r i n e
`
`ethambutol
`
`methotrexate
`t e t r a c y c l i n e
`Methods f o r reducing t h e u s u a l doses of these drugs for
`p a t i e n t s r e q u i r i n g c h r o n i c d i a l y s i s have been p u b l i s h e d
`i n v a r i o u s p l a c e s and are now s t a n d a r d p r a c t i c e (1-4).
`
`313
`Copyright 0 1977 hy Marcel Dekker. Inc. All Rights Reserved. Neither this work nor any part
`may be reproduced or transmitted in any form or by any means, electronic or mechanical. including
`photocopying, microfilming, and recording, or by any information storage and retrieval system.
`without permission in writing from the publisher.
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`314
`
`REIDENBERG AND DRAYER
`
`Most d r u g s , however, are n o t excreted unchanged.
`
`They a r e b i o t r a n s f o r m e d i n t h e body t o v a r i o u s metabo-
`l i t e s which are e v e n t u a l l y excreted. The major p a t h -
`ways of drug b i o t r a n s f o r m a t i o n , o x i d a t i o n and glucu-
`
`r o n i d e c o n j u g a t i o n , a p p e a r t o be normal i n r e n a l
`
`f a i l u r e . S e v e r a l minor pathways, i n c l u d i n g ester
`h y d r o l y s i s a n d r e d u c t i o n , seem slow (5). However,
`i r r e s p e c t i v e of whether t h e b i o t r a n s f o r m a t i o n pathway
`is normal o r slow, t h e end metabolic p r o d u c t s of t h e
`drug w i l l accumulate i n t h e p a t i e n t w i t h r e n a l f a i l u r e .
`
`T r a d i t i o n a l l y , t h e s e b i o t r a n s f o r m a t i o n pathways
`
`have been c o n s i d e r e d d e t o x i c a t i o n pathways. The f i n a l
`metabolites of drugs have been c o n s i d e r e d pharmaco-
`
`l o g i c a l l y i n e r t , a n d t h e i r build-up
`
`i n p a t i e n t s w i t h
`
`end stage r e n a l disease h a s been i g n o r e d . Y e t , r e c e n t
`
`s t u d i e s have d e m o n s t r a t e d pharmacologic a c t i v i t y of
`
`many drug m e t a b o l i t e s , and t h e i r a c c u m u l a t i o n i n r e n a l
`
`f a i l u r e can lead t o u n a n t i c i p a t e d e f f e c t s .
`
`Muscle weakness and t e n d e r n e s s t o g e t h e r w i t h a
`
`rise i n serum c r e a t i n e k i n a s e were n o t e d i n 5 uremic
`
`p a t i e n t s b e i n g treated w i t h 1-2g of c l o f i b r a t e d a i l y .
`
`Marked a c c u m u l a t i o n of b o t h f r e e and t o t a l c h l o r o -
`
`p h e n o x y i s o b u t y r i c a c i d , t h e a c t i v e metabolite of clo-
`f i b r a t e , was found i n t h e serum of 3 p a t i e n t s i n whom
`it was s o u g h t . When c l o f i b r a t e was s t o p p e d , t h e muscle
`
`symptoms and c r e a t i n e k i n a s e e l e v a t i o n s u b s i d e d (6).
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`EDITORIAL
`
`315
`
`Oxypurinol is a n a c t i v e metabolite of a l l o p u r i n o l
`
`t h a t is normally excreted i n t h e u r i n e . Plasma l e v e l s
`of o x y p u r i n o l i n p a t i e n t s w i t h poor r e n a l f u n c t i o n
`
`t a k i n g a l l o p u r i n o l a r e several f o l d h i g h e r t h a n t h e
`o x y p u r i n o l l e v e l s i n s u b j e c t s w i t h normal k i d n e y s .
`T h i s h a s been correlated w i t h a h i g h e r i n c i d e n c e of
`
`s i d e effects i n r e n a l f a i l u r e p a t i e n t s g i v e n a l l o p u r i -
`
`no1 t h a n i n p a t i e n t s w i t h h e a l t h y k i d n e y s ( 7 ) .
`
`Sulfonamides are b o t h e x c r e t e d unchanged and
`b i o t r a n s f o r m e d by a c e t y l a t i o n w i t h subsequent u r i n a r y
`
`e x c r e t i o n of t h e a c e t y l a t e d m e t a b o l i t e . While reduc-
`
`t i o n of u s u a l sulfonamide dosage c a n keep t h e plasma
`
`sulfonamide l e v e l i n t h e u s u a l r a n g e i n p a t i e n t s w i t h
`
`poor r e n a l f u n c t i o n , it cannot p r e v e n t t h e plasma
`
`l e v e l s of a c e t y l s u l f o n a m i d e from r i s i n g t o h i g h e r t h a n
`
`u s u a l l e v e l s . Adam and Dawborn observed h i g h a c e t y l -
`
`sulfonamide l e v e l s i n a l l 4 p a t i e n t s w i t h very poor
`
`r e n a l f u n c t i o n i n t h e i r s t u d y and c o r r e l a t e d t h i s w i t h
`
`d r u g - r e l a t e d nausea a n d vomiting i n three of t h e
`
`p a t i e n t s (8).
`
`Meperidine is normally metabolized t o normeperi-
`d i n e which may t h e n be e i t h e r e x c r e t e d i n t h e u r i n e or
`
`f u r t h e r metabolized. Normeperidine h a s been shown i n
`a n i m a l s t o have less a n a l g e s i c potency b u t more con-
`
`v u l s a n t potency t h a n meperidine. P a t i e n t s w i t h r e n a l
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`316
`
`REIDENBF3G AND DRAYER
`
`f a i l u r e g i v e n meperidine f o r p o s t - t r a n s p l a n t a t i o n
`
`a n a l g e s i a have marked accumulation of normeperidine
`a f t e r a f e w d o s e s of t h e p a r e n t drug. Two p a t i e n t s
`
`w i t h poor r e n a l f u n c t i o n r e c e i v i n g meperidine and
`
`having s i g n s and symptoms of c e n t r a l nervous s y s t e m
`
`i r r i t a b i l i t y had h i g h normeperidine l e v e l s . The meper-
`i d i n e was s t o p p e d , and t h e c e n t r a l nervous s y s t e m
`i r r i t a b i l i t y s u b s i d e d . T h i s d e c l i n e i n CNS i r r i t a b i l i t y
`
`seemed t o p a r a l l e l t h e f a l l of normeperidine l e v e l s in
`t h e one p a t i e n t i n whom i t was measured (9).
`Procainamide is e x c r e t e d unchanged or a c e t y a t e d
`to N-acetylprocainamide which is t h e n e l i m i n a t e d from
`
`t h e body by u r i n a r y e x c r e t i o n . N-Acetylprocainamide
`has a n a c t i o n on t h e h e a r t t h a t is similar t o procain-
`amide (10-12).
`P a t i e n t s w i t h r e n a l f a i l u r e r e c e i v i n g
`
`procainamide a t dosages a p p r o p r i a t e l y reduced t o c o r r e c t
`for t h e slower t h a n normal e l i m i n a t i o n of procainamide
`s t i l l had marked accumulation of N-acetylprocainamide.
`The i n t e n s i t y of e f f e c t observed, both t h e r a p e u t i c and
`t o x i c , w a s c l e a r l y r e l a t e d t o t h i s m e t a b o l i t e accumu-
`
`l a t i o n a s w e l l as t h e procainamide i t s e l f ( 1 3 ) .
`
`These examples demonstrate t h a t c l o f i b r a t e , a l l o -
`
`p u r i n o l , sulfonamides, meperidine, and procainamide
`
`are biotransformed t o a c t i v e m e t a b o l i t e s t h a t accumu-
`
`l a t e and produce e f f e c t s i n p a t i e n t s w i t h poor r e n a l
`
`f u n c t i o n . A g r e a t many o t h e r drugs are known t o have
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`EDITORIAL
`
`317
`
`a c t i v e metabolites (14). For many of t h e s e a c t i v e
`
`m e t a b o l i t e s , u r i n a r y e x c r e t i o n is a major pathway of
`
`normal e l i m i n a t i o n . The accumulation of t h e s e metabo-
`
`l i t e s can be p r e d i c t e d i n r e n a l f a i l u r e p a t i e n t s and
`
`t h e i r e f f e c t s a n t i c i p a t e d . More i n f o r m a t i o n about
`a c t i v e drug metabolites and t h e i r accumulation i n renal
`
`f a i l u r e c a n lead t o more p r e d i c t a b l e dose-response
`
`r e l a t i o n s h i p s and t h e r e b y better drug t h e r a p y f o r t h i s
`
`group of p a t i e n t s .
`
`Marcus M. Reidenberg, M.D.
`
`Dennis E. Drayer, Ph.D.
`
`Departments of Pharmacology and
`Medicine and t h e Rogosin Kidney
`C e n t e r , The New York H o s p i t a l -
`C o r n e l l Medical C e n t e r , New York,
`N.Y. 10021
`
`REFERENCES
`
`1. M. Reidenberg, Renal F u n c t i o n and Drgg Action,
`Saunders, P h i l a d e l p h i a , 197'1.
`
`2 . D e t t l i , L., Medical C l i n i c s of North America,
`58:977, 1974.
`3. B e n n e t t , W.M., S i n g e r , L., and Coggins, C . J . ,
`S.A.M.A., =:1544,
`1974.
`
`4 . R . J . Anderson, J.G. Gambertoglio, and R.W. S c h r i e r ,
`C l i n i c a l U s e of Drugs i n Renal F a i l u r e , Thomas,
`S p r i n g f i e l d , I l l . , 1976.
`
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`318
`
`RELDENBFXG AND DRAYER
`
`-
`5. Reidenberg, M.M., C l i n i c a l Nephrology, 4:83, 1975.
`6 . P i e r i d e s , A.M., Alvarez-Ude, F., Kerr, D.N.S.,
`and S k i l l e n , A.W., L a n c e t , 2:1279, 1975.
`7. E l i o n , G.B., Yu, T., Gutman, A.B., a n d H i t c h i n g s ,
`G.H., A m e r . J . Med., %:69, 1968.
`-
`8 , Adam, WY.R., a n d Dawborn, J . K . , Aust. Ann. Med.,
`19:250, 1970.
`9. S z e t o , H,, I n t u r r i s i , C . , Houde, R . , S a a l , S.,
`-
`Ckeigh, J . , a n d Reidenberg, M , C l i n . R e s . , 24:
`258.4, 1976.
`10, Drayer, DOE., Reidenberg, M O M s 9 a n d Sevy, R.W.,
`P r o c . SOC. Exper. B i o l . Med., 146~358, 1974.
`A . J . , Jr., C l i n . Pharmacol. T h e r . , - 17:134, 1975.
`11. E l s o n , J , , S t r o n g , J . M . , L e e , W.-K.,
`and A t k i n s o n ,
`1 2 . L e e , W.-K.,
`S t r o n g , J . M . , Kehoe, R.F., D u t c h e r ,
`-
`JoS., a n d A t k i n s o n , A . J . , Jr., C l i n . Pharmacol.
`T h e r . , P9:508, 1976.
`13. Drayer, D.E., Lowenthal, D.T., Woosley, R.L.
`N i e s , A.S., Schwartz, A.,
`and Reidenberg, M.M.,
`A b s t r a c t s , N i n t h Annual Meeting of American
`S o c i e t y of Nephrology, 1976, p. 11.
`1 4 . D r a y e r , D.E., C l i n i c a l P h a r m a c o k i n e t i c s ,
`
`i n p r e s s .
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