Ains and Warfarin2

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8/16/2019 Ains and Warfarin2 http://slidepdf.com/reader/full/ains-and-warfarin2 1/15 Journal of Pharmacokinetics and Biopharmaceutics, Vol. 1, No. 6, 1973 Kinetics of Drug Drug Interactions 1 Malcolm Rowland 2 and Shaikh B M atin 2 Since many drug-drug pharmacokinetic interactions are dependent on the concentrations of the interacting species, the degree of interaction should be a graded phenomenon varying with drug and/or metabolite concentration and thus drug administration and time. Hence one should be able to develop predictive kinetic models for such interactions. A change in drug plasma levels when a compound is administered as a single dose together with another drug can arise .from a change drug clearance, displacement from binding sites, a change in elimination rates, or a combination of any or all of these possibilities. The interaction of phenobarbital and the sparingly soluble oral antifungal agent, griseofulvin, is one example. Analysis shows that there is no change in elimination half-I fe of griseofulvin but that phenobarbital reduces the extent of griseofulvin absorption rather than enhances its elimination. Sulfaphenazole inhibits the metabolism and markedly prolongs tolbutamide plasma levels. An anticipated sudden drop in the excretion rate of the tolbutamide metabolites at maximum sulfonamide plasma levels is associated with an almost complete block of totbutamide oxidation. The inhibitor constant Klfor this interaction has been calculated, allowing one to predict tolbutamide and metabolite levels when the inhibitor is administered. Drug-drug interaction resulting from protein displacement has been hypothesized by a number of authors. However, the potentiation of the anticoagulant warfarin in patients receiving phenylbutazone is more complicated than has been envisioned previously. While displacement occurs, data suggest that phenylbutazone primarily acts through selective inhibition to alter the isomeric composition and potency of the racemic warfarin administered. The warfarin-phenylbutazone interaction study stresses the importance of measuring metabolites as well as intact drug. KEY WORDS drug-drug interactions; plasma protein displacement; griseofulvin-pheno- barbital interaction; tolbutamide sulfaphenazole interaction; Michaelis Menten kinetics; inhibitor constants; tolbutamide metabolites; warfarin-phenylbutazone interaction. Open any current medical journal and one is reminded that the co administration of two or more drugs can either cause deleterious effects or Much of the work reported in this paper was supported by a grant from the National Institutes of Health, Bethesda, Maryland, NIGMS 16496. aThis paper was presented by Dr. Rowland at the Conference on Pharmacology and Pharma- cokinetics: Problems and Perspectives, October 30-November 1, 1972, at the Fogarty Inter- national Center, National Institutes of Health, Bethesda, Maryland. This paper, in a slightly different format, will be published in the Proceedings of the Conference by Plenum Press, New York. ZSchool of Pharmacy, University of California, San Francisco, California 94143. 553 9 1973 Plenum PublishingCorporation, 227 West 17th Street, New York, N.Y. 10011. 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, microfilming,recording, or otherwise, without written permission of the publisher.

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    Jou rna l o f Pha rm aco kine t ics and Biopharmaceut ics , Vol . 1 , No. 6, 1973

    K i n e ti cs o f D r u g D r u g I n te r a ct io n s 1

    M a l c o l m R o w l a n d 2 a n d S h a i k h B M a t i n 2

    Si nce many drug-drug pharmacok i ne t i c i n t e rac t i ons are dependent on t he concent ra t i ons o f t he

    i n t e rac ti ng spec ie s, t he degree o f i n te rac t i on shoul d be a graded pheno menon vary i ng w i t h drug

    and/ or m e t abol i te concen t ra t ion and t hus drug a dmi n i s t ra t ion and t ime . H ence one shoul d be ab le t o

    deve lop predict ive kinet ic models fo r such interactions. A change in drug plasma levels when a

    compound i s adm inis tered as a s ingle dose together wi th an other drug can ar i se . from a change

    drug c learance , di spla ceme nt f ro m binding s i tes , a change in e l iminat ion rates , or a combina t ion of

    any o r al l of these poss ibi li ti es . Th e inter ac t ion of p heno barb i tal and the spa ringly soluble oral

    an ti fung al agent , griseofulvin, is one exam ple. A na lysis sho ws tha t there is no change in el imination

    hal f- I f e of gr i seofulv in but tha t phen oba rbi tal reduces the ex te nt o f gr i seofulv in absorpt ion rather

    than enhances i t s e liminat ion. Sul faph enazo le inhibi ts the me tabol i sm and m arked ly prolongs

    t o l bu t ami de p l asma l evel s. A n an t i c i pa t ed sudden drop i n t he exc re t i on ra t e o f t he t o l bu t ami de

    meta bol i tes at maxim um sulfonamide plasma leve ls i s assoc iated wi th an almost comp le te block of

    t o t bu t ami de ox i da t ion . The i nh i b i tor cons t an t K l f o r t h i s i n t e rac t ion has been ca lcu la ted , a l l ow ing

    one to predic t tolbuta mid e and m etabo l i te levels when the inhibi tor is adminis tered. Dr ug-d rug

    i n t e rac ti on re su l t ing f rom pro t e i n d i sp lacement has been hypo t hes i zed by a nu mber o f au thors .

    How ever , t he po t en t i a t i on o f the an t i coagu l an t war f ar i n in pa t i en t s rece iv ing pheny l bu t azon e i s

    more com pl icated than has been envis ioned prev iously . W hi le di splacement occurs , data sugg est that

    phenylbutazone pr imari ly ac ts through se lec t ive inhibi t ion to al ter the i someric composi t ion and

    pot ency o f the racemi c war f ar i n admin is te red . The war f ar i n-p heny l bu t azo ne i n t e rac t ion s t udy

    stresses the importan ce of measuring meta bol i tes as well as intac t drug.

    K E Y W O R D S

    drug-drug interactions; plasma protein displacement; griseofulvin-pheno-

    barbital interactio n; to lbuta mide sulfaphenazo le intera ction; Michaelis Menten kinetics;

    inhibitor constants; tolbutamide metabolites; warfarin-phenylbutazone interaction.

    O p e n a n y c u r r e n t m e d i c a l j o u r n a l a n d o n e is r e m i n d e d t h a t t h e c o

    a d m i n i s t r a t i o n o f t w o o r m o r e d r u g s c a n e i t h e r c a u s e d e l e t e r i o u s e ff ec ts o r

    Much of the work reported in this paper was supported by a grant from the National Institutes

    of Health, Bethesda, Maryland, NIGMS 16496.

    aThis paper was presented by Dr. Rowland at the Conference on Pharmacology and Pharma-

    cokinetics: Pro blems and Perspectives, October 30- Nov embe r 1, 1972, at the Foga rty Inter-

    nation al Center, Nati onal Institutes of Health, Bethesda, Maryland. This paper, in a slightly

    different format, will be published in the Proceedings of the Conference by Plenum Press,

    New York.

    ZSchool of Phar macy, University o f California, San Francisco, California 94143.

    553

    9 1973 Plenum Publishing Corporation, 227 West 17th Street, New York, N.Y. 10011. 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, microfilming, recording, or otherwise, without written permissionof the publisher.

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    K i n e t i c s o f D r u g D r u g I n t e r a c t io n s

    cy la m ide (14 ) ind ica te so m e o f the com plex i t ie s . Se ll e rs and K oc h-W ese r (15 )

    h a v e d i s c u s s e d s e v e r a l q u a n t i t a t i v e a s p e c t s o f t h e a u g m e n t a t i o n o f w a r f a r i n

    c o a g u l a t i o n i n d u c e d b y c o n c o m i t a n t c h l o r a l h y d r a t e a d m i n i s tr a t i o n , w h i c h

    m i g h t r e s u lt f r o m d i s p l a c e m e n t o f t h e a n t i c o a g u l a n t f r o m b i n d i n g s ite s, b u t

    the i r s were equ i l ib r ium ra the r th an k ine t i c cons ide ra t i6ns . Th e in ten t o f the

    p r e s e n t r e v i e w is t o i l l u st r a te h o w p h a r m a c o k i n e t i c a n a l y si s l ea d s t o f u r t h e r

    ins igh t s r ega rd ing the causes , pos s ib le mech an i sms , a nd d es ign o f fu tu re

    expe r ime n ts a im ed a t e luc ida t ing va r ious f ace t s o f d rug in te rac t ions . I t is a l so

    t h e i n t e n t t o i ll u s tr a te h o w p r e d i c t i v e p h a r m a c o k i n e t i c m o d e l s o f d r u g

    i n t e r a c t io n s c a n b e d e v e l o p e d a n d t h e p o t e n t i a l u t il it y o f s u c h m o d e l s i n

    d e c i d in g a p p r o p r i a t e d o s a g e r e g im e n s w h e n a c o m b i n a t i o n o f d r u g s is d e e m e d

    a t h e r a p e u t i c n e c e s si ty . F o r t h e m o s t p a r t , t h e e x a m p l e s c h o s e n a r e f r o m t h e

    a u t h o r s o w n r e s e a r c h e x p e ri e n ce .

    M u c h o f t h e i n t e r p r e t a t io n o f d r u g - d r u g i n t e ra c t i o n s a r i se s fr o m c a r e fu l

    m e a s u r e m e n t s o f t h e c o n c e n t r a t i o n t i m e c o u r s e o f a d r u g o r i ts m e t a b o l i te . A

    d e c r e a s e i n d r u g p l a s m a l ev e ls w h e n a d m i n i s te r e d a s a si n gl e d o s e t o g e t h e r

    w i t h a n o t h e r d r u g c o u l d a r i s e f r o m a r e d u c t i o n i n a b s o r p t i o n ( if t h e d r u g i s

    g i v e n o t h e r t h a n i n t ra v e n o u s l y ) , d i s p l a c e m e n t f r o m p l a s m a p r o t e i n s, h a s t e n -

    ing o f i ts e l im ina t ion , o r a com bin a t io n o f any o r a l l o f these pos s ib i l it i e s.

    K i n e t i c a n a l y s is h a s h e l p e d g r e a t l y in th e i n t e r p r e t a t i o n o f s u c h d a t a a n d h a s

    s u g g e s t e d t h e d e s ig n o f f u r th e r e x p e r im e n t s . T h e i n t e r a c t i o n b e t w e e n t h e

    spar ing ly so lub le o ra l an t i funga l agen t , g r i s eo fu lv in , and phenobarb i t a l i s

    o n e e x a m p l e . B u s h f ie l d e t a l (16 ) had no ted tha t p lasm a l evel s o f g r i s eo fu lv in

    f o l lo w i n g a s in g le d o s e o f t h is d r u g w e r e r e d u c e d i n s u b j e c t s c o a d m i n i s t e r e d

    p h e n o b a r b i t a l . G r i s e o f u l v i n i s p r i m a r i l y O - d e m e t h y l a t e d t o 6 - d e m e t h y l -

    g r i s e o f u l v i n i n m a n , a n d i t w a s p r o p o s e d t h a t p l ~ n o b a r b i t a l h a d s t i m u l a t e d

    t h i s o x i d a t i v e p a t h w a y . A n a l y s i s b y R i e g e l m a n

    e t a l

    ( 1 7 ) s h o w e d t h a t t h e r e

    wa s no cha nge in the e l im ina t ion ha l f- li fe o f g r i seo fu lv in and l ed the m to

    d e s ig n a s t u d y t o p r o v e t h a t p h e n o b a r b i t a l r e d u c e d t h e e x t e n t o f g r i se o f u lv i n

    ab so rp t i on r a the r th an e nha nce d i t s e l imina t ion (Fig . 1 ). The r edu ced ab -

    s o r p t i o n w a s c o m p l e m e n t e d b y a p r o p o r t i o n a l r e d u c t io n i n t h e c u m u l a t iv e

    u r i n a r y e x c r e t i o n o f 6 - d e m e t h y l g r is e o f u lv i n . T h e m e c h a n i s m o f t h e i n t er a c -

    t i o n i s p o o r l y u n d e r s t o o d . P r e s u m a b l y , p h e n o b a r b i t a l d i m i n i s h e s t h e r a t e o f

    d i s s o l u t i o n o f t h is s p a r i n g l y s o l u b l e a n d i n c o m p l e t e l y a b s o r b e d d r u g , p e r h a p s

    b y d e c r e a s i n g g u t m o t i l it y o r i n t e s t in a l t r a n s it t im e . T h e s e d a t a s u g g e st t h a t

    a m o r e r a p i d l y d i s s o l v i n g g r i s e o f u l v i n f o r m u l a t i o n s h o u l d o b v i a t e t h e

    p r o b l e m . P r o b a b l y , b y t h e s a m e o r a s i m i la r m e c h a n i s m , b a r b i t u r a t e s d e -

    c r e a s e t h e a b s o r p t i o n o f t h e s p a ri n g l y s o l u b l e a n t i c o a g u l a n t , d i c o u m a r o l

    (18 ) . C l in ica l ly , the danger a r i s es when the ba rb i tu ra te i s w i thd rawn f rom a

    p a t i e n t s t a b i l i z e d o n t h i s a n t i c o a g u l a n t - b a r b i t u r a t e c o m b i n a t i o n . I n n o n e

    o f t h e s e s t u d ie s w e r e p l a s m a b a r b i t u r a t e c o n c e n t r a t i o n s d e t e r m i n e d , a n d

    henc e i t is d i f fi cu lt to kn ow wh e the r the s ever i ty o f the dep re s s ion o f the

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    556

    owland and

    M a t i n

    INTRAVENOUS 9 9

    2.0-- ORAL I I 0

    CONTROL WITH

    . ~ J ~ PHENOBARBITAL

    o

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    HOURS

    F ig . 1 . G r i s e o f u l v i n - p h e n o b a r b i t a l i n t e r a c t i o n

    i n m a n . N o t e t h a t t h e d i s p o s i t i o n k i n e t i c s o f

    g r i s e o f u l v i n g i v e n i n t r a v e n o u s l y a r e u n a f f e c t e d

    b y p h e n o b a r b i t a l a d m i n i s t r a t i o n . I n c o n t r a s t ,

    b o t h t h e r a t e a n d e x t e n t o f o r a l g r i s e o f u l v i n a r e

    d e p r e s s e d f o l l o w i n g p h e n o b a r b i t a l . R e p r o d u c e d

    f r o m R i e g e l m a n e t a l 1 7 ) w i t h p e r m i s s i o n o f t h e

    c o p y r i g h t o w n e r s .

    extent of absorption of either griseofulvin or dicoumarol among or within

    subjects could be correlated with the amount of barbiturate in the body.

    Nonetheless, some relationship between the effect and the body burden of

    barbiturate is anticipated.

    A more clearly defined and more readily modeled interaction is that

    between the oral hypogtycemic agent, tolbutamide, and a variety of drugs.

    Together with the anticoagulants, interactions with the oral hypoglycemic

    agents constitute some of the most adverse clinical cases of drug interactions.

    Hypoglycemic crises have been reported when patients, stabilized on tol-

    butamide, have added sulfaphenazote, dicoumarol, phenylbutazone, or

    phenyramidol to their drug therapy 19, 20). In each case cited, clear chemical

    data exist showing a slowing a tolbutamide elimination. Many of these

    interactions appear to involve inhibition of tolbutamide oxidation to

    hydroxytolbutamide, which is virtually obligatory for tolbutamide elimina-

    tion in man 21). Hydroxyto lbutamide is partially excreted unchanged, and

    the majority is further oxidized to carboxytolbutamide, which is excreted

    intact. The oxidation of tolbutamide is the rate-limiting step in the elimina-

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    Kinetics of Drug Drug Interactions 557

    tion of the drug and its metabolites. Subsequent oxidation steps are very

    rapid 22). Accordingly, a short time after tolbutamide administrat ion, the

    rate of excretion of the sum of the two metabolites equals the rate of tol-

    butamide oxidation and offers a very sensitive measure of changing tolbuta-

    mide oxidation.

    The best-studied interaction is that between the sulfonamide, sulfa-

    phenazole, and tolbutamide. While not widely prescribed, sulfaphenazole

    is reported to increase the half-life of tolbutamide from the normal 4-8 hr to

    values ranging from 24 to 70 hr 22, 23). The clinical crises probably arise

    when tolbutamide accumulates upon chronic administrat ion in the presence

    of sulfaphenazole. Figures 2 and 3 illustrate the situation when sulfaphenazole

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    F ig . 2 . T o l b u t a m i d e - s u l f a p h e n a z o l e i n t e r a c t i o n k i n e t ic s i n m a n .

    T h e e x p e r i m e n t a l d a t a ( t o l b u t a m i d e , s u l f a p h e n a z o l e ) a n d t h e

    a n a l o g c o m p u t e r g e n e r a t e d c u r v e s ( s o l i d l i n e s ) d e s c r i b e t h e

    i n t e r a c t i o n b e t w e e n s u l f a p h e n a z o l e a n d t o l b u t a m i d e . T h e

    s u b j ec t r e ce iv e d a n i n t r a v e n o u s b o l u s o f 1 g t o l b u t a m i d e a n d a

    1 g ora l susp ens i on of su l faphe nazo l e (Su l fab i dR) 589 hr l a t e r.

    F o r c o n v e n i en c e , t h e a m o u n t o f t h e t w o d r u g s i n th e b o d y i s

    e x p r e s s e d a s a p e r c e n t a g e o f t h e a d m i n i s t e r e d d o s e . T h e h a l f-

    l if e o f t o l b u t a m i d e i n t h e a b s e n c e o f s u l f a p h e n a z o l e i s a p p r o x i -

    m a t e l y 7 h r . T h e d o t t e d l i n e s d e p i c t t h e a n t i c i p a t e d r a p i d d e c l i n e

    o f t o l b u t a m i d e w h e n a d m i n i s t e r e d a lo n e . T h e d e g r e e o f i n -

    h i b i t i o n o f t o l b u t a m i d e o x i d a t i o n c o n t i n u o u s l y c h a n g e s w i t h

    t h e a m o u n t o f s u l f a p h e n a zo l e in t h e b o d y . B l o c k is m a x i m a l a t

    p e a k s u l f o n a m i d e p l a s m a le ve ls , T h e h a lf - li fe o f s u l f a p h e n a z o l e

    i n t h i s sub j ec t i s 12 hr .

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      8 R ow lan d an d Ma t in

    100.0

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    C o r b o x y t o l b u t a m i d e

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    I.V) oral)

    TIME hours)

    F ig . 3 . T o l b u t a m i d e - s u l f a p h e n a z o l e i n t e r a c t i o n k in e t i c s i n m a n . T h e e x c r e t io n r a t e d a t a

    o f h y d r o x y t o l b u t a m i d e a n d c a r b o x y t o l b u t a m i d e f o r t h e s a m e s u b je c t w h o s e p l a s m a d a t a

    a r e p o r t r a y e d i n F i g . 2 . A t p e a k p l a s m a s u l f a p h e n a z o l e l ev els , t h e i n h i b i t i o n o f t o l b u t a -

    m i d e o x i d a t i o n i s a l m o s t c o m p l e t e, a n d , w i th e s s e n ti a ll y n o f o r m a t i o n o f h y d r o x y t o l -

    b u t a m i d e , t h e e x c r e t i o n r a t e o f b o t h t h i s m e t a b o l i t e a n d c a r b o x y t o l b u t a m i d e r a p i d l y

    fal l, r ef l ec ti ng t he ve ry sho r t 20-4 0 m i n) ha l f -l i ve s o f the se spec ie s. Bey ond 10 hr a f t e r t he

    t o l b u t a m i d e b o l u s , t h e r a t e o f e x c r e t io n o f t h e s e t o l b u t a m i d e m e t a b o l i t e s e q u a l s t h e r a t e

    o f to l b u t a m i d e o x i d a t i o n . A s t h e s u l f a p h e n a z o l e b o d y l e v e l s d e c l in e , t h e d e g r e e o f

    i n h i b i t io n o f t o l b u t a m i d e o x i d a t i o n d i m i n i sh e s a n d t h e e x c r e t io n r a t e o f t h e m e t a b o l it e s

    i n c re a s es . H o w e v e r , e v e n t h o u g h t h e i n h i b i t i o n c o n t i n u a l l y d i m i n i s h e s , s o a l s o d o e s t h e

    a m o u n t o f t o l b u t a m i d e i n t h e b o d y , a n d a f t e r 5 0 h r t h e e x c r e t i o n r a te o f m e t a b o l i t e s c o n -

    t inual ly dec l ines , a lbe i t s lowly.

    is g iven o ra l ly to a sub jec t app rox im ate ly 5 h r a f t e r r ece iv ing an in t r av eno us

    b o l u s d o s e o f t o l b u ta m i d e . S u l fa p h e n a z o le m a r k e d l y p r o l o n g e d t o l b u t a m i d e

    p lasm a l eve ls , w i th an an t i c ipa ted sudd en d r op in the excre t ion r a te o f the

    m e t a b o l i t e s a t m a x i m u m s u l f o n a m i d e p l a s m a l e v el s a s s o c i a t e d w it h a n

    a l m o s t c o m p l e t e b l o c k o f t o l b u t a m i d e o x i d a t i o n . T h e h a lf -l iv e s f r o m t h i s

    s h a r p ly d e s c e n d in g p o r t i o n o f t h e h y d r o x y a n d c a r b o x y t o l b u t a m i d e u r i n a r y

    e x c r e t io n r a t e p l o t s a p p r o x i m a t e d t h e h a lf -l iv e s o f t h e s e m e t a b o l i t e s w h e n

    a d m i n i s t e r e d a l o n e 2 2 ). A s t h e r a t i o o f h y d r o x y - to c a r b o x y t o l b u t a m i d e i n

    t h e u r i n e r e m a i n e d u n c h a n g e d i n th e p r e s e n c e o f s u l fa p h e n a z o l e , i t a p p e a r s

    t h a t t h is s u l f o n a m i d e d o e s n o t i n f lu e n c e th e o x i d a t i o n o r r e n a l c l e a r a n c e o f

    h y d r o x y t o l b u t a m i d e i n t h e d o s e r a n g e s t u d i e d . S e p a r a t e s t u d i e s c o n f i r m e d

    tha t to lbu tam ide 1 g ) d id no t in f luence su l f aphen azo le e l imina t ion k ine t ic s ,

    wh ich is p r inc ipa l ly by NX -g lucuron ida t ion and N 4-ace ty la t ion 24 ).

    H u m a n in v i tro l iv e r m i c r o s o m a l s t u d i e s c o n f i rm e d t h a t s u l f a p h e n a z o l e

    b loc ks to lb u ta m ide ox id a t ion 19 ) , wh ich , a t l eas t in the r ab b i t 25 ) , i s by

    com pet i t ive inh ib i tion . T he k ine t ic s o f com pet i t ive inh ib i t ion o f a g iven

    m etab o l i t e s t ep is genera l ly g iven by 26 )

    R a te o f m e tab o l i sm = V ,n- S 1 )

    S + K i n 1 + I / K I )

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    K i n e t i c s o f D r u g D r u g I n t e r a c t io n s 5 5 9

    where Vm is the maximal velocity of the reaction, Km is the Michaelis-Menten

    constant, S is the substrate concentration, I is inhibitor concentration, and

    K t

    is the inhibitor constant, given by the value of I which increases the apparent

    K mof the system by twofold. In the particular case of tolbutamide, the rate of

    oxidation to hydroxytolbutamide virtually equals the rate of tolbutamide

    elimination. Also, as tolbutamide half-life does not change over 0.5-6.0 g dose

    range 27), the concentration of drug at the metabolic site must always be

    much smaller than its Kin. With these facts, and knowing that in the absence

    of sulfaphenazole the decay of tolbutamide can be described by a first-order

    process, rate constant

    k r ,

    the following simple description can be given for the

    elimination kinetics of tolbutamide in the presence of the inhibitor, sulfa-

    phenazole :

    k r T

    Rate of tolbutamide elimination = - d T / d t ) - 1 + I / K ~ ) 2)

    where T and I are the amounts oftolbutamide and sulfaphenazole in the body,

    and K~ may now be defined as the amount of inhibitor which diminishes the

    effective k T by one-half or prolongs the half-life twofold). By measuring all

    chemical species, only K~ remains unknown. In the present data, an excellent

    fit is obtained when Kt is 200 mg sulfaphenazole Fig. 2). This value of 200 mg

    is small compared to the 1-2 g daily dose usually recommended for this

    sulfonamide.

    Knowing the Kt for sulfaphenazole and the other relevant pharmaco-

    kinetic data, the clinical situation can be modeled. Usually, 0.5 g tolbutamide

    and 1.0 g sulfaphenazole are given orally twice daily. Initially when only

    tolbutamide is given, expected plateau levels are reached within 3-4 half-

    lives 28), or 30 hr Fig. 4). When sulfaphenazole is also given, it accumulates

    and also blocks tolbutamide oxidation, causing a rise in the level of the

    sulfonylurea to approximately seven times its usual level. A time period of 2-3

    days is required before this elevated tolbutamide level falls to the level in the

    absence of sulfaphenazole, regardless of whether only sulfaphenazole or both

    drugs are stopped. These data can adequately explain the elevated tolbuta-

    mide levels seen when these two drugs are administered concomitantly for

    extended periods 19, 23).

    The exact estimate for the new half-life of tolbutamide, and the degree of

    accumulation in the presence of a steady level of the inhibitor, is gained from

    two equations 29) :

    Average amount of drug in the body at the plateau 4)

    3 )

    1.44 x dose x half-life

    dosing interval

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    5 6 R o w l a nd a nd M a t i n

    g

    > -

    o

    Z

    7_

    E

    6

    4

    i

    j

    0

    ~ ':?

    7 1 4 2 1

    T I M E d a y s)

    Fig. 4, To lbutam ide-sulfaph enazole interaction kinetics in m an.

    A nalo g computer simulations of the clinical situatio n when

    tolbutamide 0.5g, twice daily) is given in the absence and

    presence of sulfaphenazole 1.0 g twice daily). The so lid b lack

    bars denote the dura tion o f each drug regimen. Having a short

    half-life 4-8 hr), plateau levels of tolbuta m ide are reached within

    2 days. The sulfaphenazole also rapidly reaches plateau con-

    cen tratio n half-life 11~12 hr). In the presence ofsulfaphenazole,

    the am ount of tolbuta mid e in the bod y continues to rise until

    out put once again equals input. U pon cessation o f sulfaphena-

    zole, the decline of tolbu tam ide, whether contin ued solid line)

    or stop ped at the same time as sulfaphenazole dott ed line), is

    prim arily controlled by the ra te of remov al o f sulfaphenazole .

    Consequently, it would take several days before to[butamide

    levels once again fe ll into the accepted thera peu tic range.

    T h e n e w s t e a d y - s t a t e t o l b u t a m i d e h a l f - li fe i s

    T o l b u t a m i d e t l / 2 ( i n h i b i t e d ) = t o l b u t a m i d e tl/2 no rm ,j )

    4 )

    a v e r a g e a m o u n t o f i n h i b i t o r a t p l a t e a u )

    x 1 + K I

    I f s u l f a p h e n a z o l e t l / 2 = 1 0 h r , K I = 2 0 0 m g ) 2 5 ) i s g i v e n a s 1 .0 g t w i c e

    d a i l y , t h e n a c c o r d i n g t o t h e f i rs t e q u a t i o n , 1.5 g is t h e a v e r a g e a m o u n t o f

    i n h i b i t o r a t t h e p l a t e a u a n d t h is l ev e l is r e a c h e d w i t h i n 2 d a y s 4 x

    t l / z ) .

    S u b s t i t u t i n g t h i s a m o u n t o f t h e i n h i b i t o r i n t o e q u a t i o n 4 in d i c a te s t h a t t h e

    n e w h a l f - li f e f o r t o l b u t a m i d e is s e v e n t o e i g h t t i m e s l o n g e r t h a n n o r m a l i .e .,

    f r o m 3 5 t o 40 h r i n s t e a d o f 5 h r) . N o w i t w i l l t a k e a p p r o x i m a t e l y 6 d a y s

    4 x 1 .5 d a y s ) to r e a c h t h e n e w p l a t e a u w h e n t h e a v e r a g e a m o u n t o f t o l -

    b u t a m i d e is s e v e n t o e i g h t t i m e s t h e a v e r a g e p l a t e a u l ev e l i n th e a b s e n c e o f t h e

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    Kinetics of Drug Drug Interactions 5 6 1

    i n h i b it o r . I t w a s g r a t i fy i n g t o n o t e t h a t t h e se p r e d i c t io n s , w h e n a p p r o p r i a t e l y

    s c a l e d d o w n , w e r e o b s e r v e d i n a s u b j e c t w h o r e c e i v e d t h e s a m e m u l t i p l e

    d o s e s c h e d u l e a s d e p i c t e d i n F i g . 4 w i t h t h e e x c e p t i o n t h a t 0 . 1 g r a t h e r t h a n

    0 .5 g t o l b u t a m i d e w a s i n g e s t e d e a c h d a y (2 5) . I f i t w e r e n e c e s s a r y t o g i ve th e s e

    t w o d r u g s i n c o m b i n a t i o n , it is a p p a r e n t t h a t t h e d o s a g e s c h e d u l e o f t o l b u t a -

    m i d e w o u l d h a v e t o b e r e d u c e d o n e - e i g h t h t o m a i n t a i n e s s e n t ia l ly t h e s a m e

    a m o u n t o f t o l b u t a m i d e i n t h e b o d y . I n a n y i n d i v id u a l , t h e d e g re e o f i n te r a c -

    t i o n w i ll d e p e n d u p o n t h e d o s a g e r e g i m e n o f e a c h d r u g , t h e h a lf -l if e f o r e a c h

    d r u g , a n d t h e K t i n t h a t i n d i v i d u a l . A t t h i s s ta g e , t h e v a r i a t i o n o f K ~ w i t h i n

    t h e p o p u l a t i o n is u n k n o w n .

    T h e e l i m i n a t i o n o f t o l b u t a m i d e in m a n is a sp e c ia l c a se o f t h e m o r e

    g e n e r a l s i t u a t i o n w h e r e d r u g is e l i m i n a t e d b y s e v e r a l p a t h w a y s i n s t e a d o f o n e .

    C o n s i d e r i n g t h e m o r e g e n e r a l s i tu a t i o n , o n e c a n d e v e l o p a m o d e l o f d r u g

    i n h i b i t i o n i n t e r a c t i o n s i n a n a n a l o g o u s m a n n e r t o t h e t o l b u t a m i d e - s u l f a -

    p h e n a z o l e - m a n m o d e l . T h e e q u a t i o n s a r e s i m i l a r t o t h o s e d e r i v e d f o r

    s c h e d u l e s o f d r u g s i n p a t ie n t s w i th v a r y i n g d e g re e s o f r e n a l i m p a i r m e n t . O n e

    n e e d s t o k n o w t h e f r a c t i o n o f t h e d o s e i n th e b o d y e l i m i n a t e d b y a p a r t i c u l a r

    p a t h w a y o f i n t e re s t i n t h e a b s e n c e o f i n h i b i t o r ( j, , ), t h e a m o u n t o f i n h i b i to r ( I ),

    a n d t h e i n h i b i t o r c o n s t a n t ( K t ) . T h e r a t i o o f t h e n e w h a lf -l if e o f th e d r u g i n t h e

    p r e s e n c e o f i n h i b i to r

    ( t l / 2 i n h i b i t e d ) t o

    t h e n o r m a l h a l f - l i f e

    t l / 2

    . . . . . 1 )

    a n d t h e

    rat__iio o f t he s t ea dy -s t a t e a m o u n t o f d r ug be fo re

    Ab

    . . . . l) a n d a f t e r i n h i b i t i o n

    (Abinhib ition) w he n a f ixe d reg im en i s ad m ini s te re d , i s g ive n b y

    R = t l 2 i n h i b i t e d / t l / Z

    1 =

    A b i n h i b i t e d A b 1

    5 )

    [fm/(1 + I / K , ] +

    I

    - fro)

    T h e i n f lu e n c e o f J ,, a n d

    I/K I

    o n t h e s e p a r a m e t e r s i s i l lu s t r a t e d i n F i g s . 5 a n d 6 .

    U n l e s s t h e t h e r a p e u t i c i n d e x o f t h e d r u g is s m a l l ( F ig . 5), a n a l t e r a t i o n i n t h e

    d o s a g e s c h e d u l e o f a d r u g i s u n w a r r a n t e d f o r f , < 0 .5 , e v e n w h e n i n h i b i t i o n

    o f t h e p a r t i c u l a r p a t h w a y is c o m p l e t e . A l so , if t h e d o s a g e s c h e d u l e is m a i n -

    t a i n e d a n d J~, > 0 .5 , a n a d v e r s e r e a c t i o n m a y b e s e e n b e f o r e th e n e w p l a t e a u

    is r e a c h e d o r , if s e e n a t t h e p l a t e a u , it m a y t a k e s o m e t i m e ( 4

    x t l / 2 i n h i b i t o r )

    a f t e r i n i t i a t i o n o f th e i n h i b i t o r r e g i m e n . A l t e r n a t i v e l y , t o p r e v e n t d r u g

    a c c u m u l a t i o n t h e d o s a g e s c h e d u le o f t h e d r u g w ill h av e t o b e r e d u c e d b y

    1/R.

    T h e s i t u a t io n w ill b e m o r e c o m p l e x w h e n t h e c o n c e n t r a t i o n o f d r u g a t t h e

    m e t a b o l i c s i t e i s g r e a t e r t h a n i t s K , , , a n d w h e n b o t h d r u g s a r e c o m p e t i t o r s

    o f o n e o r m o r e o f t h e o t h e r ' s p a t h w a y ( s ).

    T o l b u t a m i d e , a n a c i d , is s i g n if i c a n tl y b o u n d t o p l a s m a a n d p r e s u m a b l y

    t is s u e p r o t e in s . I ts h y p o g l y c e m i c a c t i v i ty p r o b a b l y is a f u n c t i o n o f t h e u n -

    b o u n d c o n c e n t r a t i o n i n t h e p l a s m a a n d t is s u e w a t e rs . S u l f a p h e n a z o l e , d i -

    c o u m a r o l , a n d p h e n y l b u t a z o n e a re a l so a c id s , h i g h l y b o u n d t o p l a s m a a n d

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    562 o wl a nd a nd M a t in

    2 0

    1 0

    f m - - I

    r n = 0 . 8

    _ / ~ ~

    m : O . 6

    [

    I [ f m : O . 4

    4 1 0 2 0

    I/K I

    Fig. 5. The effect of inhibition on the ratio R)

    of the new half-life of a drug in the presence of

    the inhibitor to the normal half-life, or to the

    ratio of the average amount of drug at the

    plateau in the presence and absence of the

    inhibitor. When all the drug is eliminated by

    the inhibited route fm = 1), the ratio changes

    dramatically with changes in inhibitor. Below

    f,, = 0.5, the maximum increase in the ratio

    is twofold and is inconsequential unless the

    drug has a narrow therapeutic index or the

    metabolite affected plays an important phar-

    macological role.

    tissue proteins, and are capable of displacing tolbutamide and one anothe r

    from albumin in

    n v t r o

    experiments 19). Because of these associations,

    protein binding displacement has been intimated as a contributory cause of

    the enhanced hypogly cemia experienced when these drugs are used in

    comb inat ion with tolbutamide. However, in the case of tolbutamide, the

    contri bution of displacement is prob abl y mino r compare d to inhibition of

    oxidation, as many other sulfonamides which displace tolbutamide from

    albumin

    n v t r o

    neither produce prolongation of its half-life nor increase its

    effect 23, 30). Nonetheless, it is worthwhile to consider when disp lacement

    will significantly influence the pharmacological effect of a drug. To answer

    this question, one must know whether displacement is from both plasma a nd

    tissue proteins, whether drug clearance depends on the total bound and

    unbound) or unbound plasma concentration, and whether the drug is given

    on a single occasion or continually.

    Appreciable drug displacement occurs when a majo r portio n of the same

    binding sites are occupied by the displacing agent. Consequently, to displace

    drugs from plasma albumin requires that the plasma conc entra tion of the

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    Kinetics of Drug Drug Interactions 5 6 3

    d i s p l a c e r a p p r o a c h o r e x c e e d 0 .6 m M , t h e c o n c e n t r a t i o n o f p l a s m a a l b u m i n .

    F o r a s u b s t a n c e w i t h a m o l e c u l a r w e i g h t o f 3 00 , t h is c o r r e s p o n d s t o

    1 80 m g / l it e r. T h e s e p l a s m a c o n c e n t r a t i o n s a r e s e e n w i th s u l f o n a m i d e s a n d

    s a l i c y l a t e s , w h i c h a r e c o m m o n l y g i v e n i n g r a m d o s e s a n d w h i c h p o s s e s s

    s m a l l v o l u m e s o f d i s t ri b u t i o n . T h e y a r e a l s o r e a c h e d w i t h p h e n y l b u t a z o n e .

    A l t h o u g h t h e n o r m a l d o s e o f t h is a n t i - in f l a m m a t o r y a g e n t i s 10 0 m g , o w i n g

    t o i t s l o n g h a l f- li fe p h e n y l b u t a z o n e a c c u m u l a t e s t o w e l l o v e r 1 g in t h e b o d y

    when g iven th ree t imes da i ly .

    P l a s m a c o n c e n t r a t i o n s e x c e e d i n g 0 .6 m ~ l a r e a l s o p r o b a b l y a c h i e v e d

    fo l lowing the r ap id in t r av eno us b o lu s l es s than 10 s ec ) o f qu i t e m od es t doses .

    The se eve n t s a r e l ike ly f l ee t ing , how ever , a s d i sp lace r m ixes w i th the v ascu la r

    sys tem an d d i s t r ibu tes ou t in to the t i ssues . Th e r ap id in jec t ion o f even l a rge r

    d o s e s m o r e th a n 1 4 m g / k g ) o f d r u g s w h i c h r e si d e p r i m a r i l y i n p l a s m a m a y

    s t i l l on ly p roduce s ign i f i can t r i s es in the unbound concen t r a t ion t r ans ien t ly

    a s d i s p l a c e d d r u g m o v e s d o w n t h e n e w l y c r e a t e d c o n c e n t r a t i o n g r a d i e n t

    ou t in to the l a rge t is sue wa te r spac e 31 ). Indeed , a s the fo l lowing ca lcu la t ion

    wi l l show, d ru g d i sp lac em en t i s un l ike ly to be c l in ica lly s ign i fi can t un les s i t is

    d i s p l a c e d f r o m a n d s u b s t a n t i a l l y b o u n d t o b o t h p l a s m a a n d t i s s u e b i n d i n g

    s it e s. T h u s t h e f r a c t i o n o f a d r u g i n t h e b o d y b o u n d t o p l a s m a p r o t e i n s is

    3 /? /Vd , w here 3 i s the p lasm a vo lu m e in l it e rs , V~ i s the vo lu m e o f d i s t r ibu t ion

    of the d rug , a l so expre s sed in lit er s, an d /3 is the f r ac t ion o f d rug in p lasm a

    b o u n d t o p l a s m a p r o t e in s . F o r a d r u g l ik e t h e a n t i c o a g u l a n t w a r f a ri n , w h i c h

    A M O U N T

    ~ N O R M )

    2 0 I KI=I9

    10

    I KI=9

    J I

    20 410 60 80 100

    TIME TY2NORM]

    [ / K [ = 4

    2

    1 KI=0

    0 I

    0 120 140

    F i g . 6 . T h e e f fe c t o f in h i b i t i o n o n t h e r a t e o f a c c u m u l a t i o n

    o f a d r u g g i v e n o n a f i x e d d o s e - f i x e d i n te r v a l r e g i m e n

    w h e n f , , = 1. N o t e t h a t t i m e f o r a c c u m u l a t i o n is ex -

    p r e s s e d i n u n i t s o f th e n o r m a l h a lf -l if e. T h e m o r e c o m -

    p l e t e t h e b l o c k , t h e l o n g e r t h e h a l f- l if e F i g . 5) a n d t h e

    l o n g e r i t t a k e s t o r e a c h t h e n e w p l a t e a u . I n c l i n i c a l

    p r a c t ic e , to x i c i ty m a y b e n o t e d b e f o r e t h e n e w p l a t e a u

    i s r e a c h e d . T h e s e c a l c u l a t i o n s a s s u m e t h a t t h e i n h i b i t o r

    a m o u n t i n th e b o d y is i m m e d i a t e l y a tt a i n e d a n d m a i n -

    t a i n e d c o n s t a n t .

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    5 6 4

    o wl a nd a nd

    M a t i n

    i s h ig h ly bo u nd (/~ = 0 .995) an d w i th a ve ry sm al l Va, a r ou nd 10 l it e r s, t h i s

    m e a n s th a t a s m u c h a s 3 0 i n t h e b o d y re s id e s o n th e p l a s m a p r o t e in s .

    N o n e t h e l e s s , e v e n i f i t w e r e c o m p l e t e l y d i s p l a c e d o f f i ts p l a s m a b i n d i n g s i te s

    (/~ --, 0 ), w i t h a d r a m a t i c d r o p i n t h e t o t a l p l a s m a c o n c e n t r a t i o n , t h i s 3 0

    a d d e d t o t h e r e m a i n i n g 70 w o u l d i n cr e as e t h e u n b o u n d c o n c e n t r a t i o n in

    t h e b o d y o n l y b y 4 2 ~o. T h i s i n c r e a se i s s m a l l c o m p a r e d t o t h e n o r m a l c h a n g e s

    i n t h e u n b o u n d c o n c e n t r a t i o n a s d r u g i s e l im i n a t e d . A n y s u b s t a n t i a l in c r e a se

    i n u n b o u n d c o n c e n t r a t io n a b o v e t h a t a n t i c ip a t e d f r o m p l a sm a d i s p la c e m e n t

    a u t o m a t i c a l l y i m p l i es t h a t t is s u e b i n d i n g i s s i g n if i ca n t a n d t h a t d i s p l a c e m e n t

    m u s t a l so h a v e o c c u r r e d .

    T h e p r e c e d i n g c o m m e n t s r e fe r t o s i t u a t i o n s w h e r e t h e d r u g is gi v en o n l y

    o n c e i n t h e a b s e n c e o r p r e s e n c e o f t h e s u s p e c t e d d i sp l a c e r. I n d r u g t h e r a p y ,

    i t i s m o r e c o m m o n t o g i v e b o t h d r u g a n d d i s p l a c e r o n a m u l t i p l e d o s e

    r e gi m e n . T h e c h a n g e s i n th e u n b o u n d c o n c e n t r a t i o n (C I) d e p e n d o n w h e t h e r

    d r u g c le a r a n c e d e p e n d s o n C o r t o ta l p l a s m a c o n c e n t r a t i o n (C v ). U p o n a

    c o n s t a n t d r u g i n t a k e ( R ~ t h e s t e a d y - s t a t e p l a s m a c o n c e n t r a t i o n (C p~s) is

    d e f i n e d b y

    R ~

    =

    C L

    C , ,

    6 )

    w h e r e C L is th e c l e a r a n c e o f t h e d r u g , o r

    R ~ = C L C A ~ 7 )

    w h e r e c~ is t h e f r a c t io n o f d r u g u n b o u n d i n p la s m a . F o r d r u g s w h i c h a r e s o le l y

    c l e a re d b y g l o m e r u l a r f i l tr a t i o n o r f o r d r u g s w h i c h h a v e v e r y l o w e x t r a c t i o n

    r a t i o s a c r o s s t h e l i v e r , c l e a r a n c e i s d e p e n d e n t o n t h e u n b o u n d p l a s m a c o n -

    c e n t r a t i o n s u c h t h a t

    C L = C L m a x 9 ~ ( 8 )

    w h e r e C L m , x is e it h e r t h e g l o m e r u l a r f i l tr a t i o n ra t e o r t h e m a x i m u m m e t a b o l i c

    c l ea ran ce w he n c~ = 1. D i sp l a cem en t , b y i nc reas ing c~, i nc reases c l ea rance .

    B u t s u b s t i t u t i o n o f e q u a t i o n 8 i n t o e q u a t i o n 6

    R ~ = C t m a x f s ~ ( 9 )

    i n d i c a t e s t h a t a t s t e a d y s t a t e , w h e n r a t e o u t b a l a n c e s r a t e i n , t h e u n b o u n d

    c o n c e n t r a t i o n s h o u l d b e c o n s t a n t a n d i n d e p e n d e n t o f th e d e g r e e o f p r o t e in

    b i n d i n g . B e t w e e n s t e a d y st a te s , t h e u n b o u n d c o n c e n t r a t i o n m a y b e g re a t e r o r

    l e s se r t h an t he Czss , d e p e n d i n g o n w h e t h e r t h e c o n c e n t r a t i o n o f t h e d i s p la c i n g

    a g e n t i s r i s in g o r f a l l in g . I n t h o s e c a s e s w h e r e c h a n g e s i n t h e d i s p l a c i n g a g e n t

    a r e s l o w , r e l a t i v e t o t h e e l i m i n a t i o n k i n e t i c s o f t h e d i s p l a c e d d r u g , t h e d r u g

    m a y b e r e g a r d e d a s b e i n g a t p s e u d o s t e a d y s ta te . T h e n , u p o n c o n s t a n t d r u g

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    13/15

    Kinetics of D rug Dru g Interactions 6

    t he r apy , t he unb ou nd con cen t r a t i on ( and p r e s um ab l y pha r m aco l og i ca l effect)

    s hou l d r em a i n con s t an t a nd app a r en t l y una f f ec t ed by t he d i sp l ac ing agen t .

    B o t h l i doca ine (32 ) and pen ic i ll in G a r e app r ec i ab l y bou nd t o p l a s m a

    pro te ins (/3 > 0 .5), and ye t each is h igh ly c leared b y the l iver and k idney ,

    r e spec ti ve ly . E v i den t l y , r emo va l o f un bo un d d r ug is s o e f fec ti ve t ha t t he d r u g -

    p r o t e i n comp l ex d i s soc i a te s a l mos t com pl e t e l y be f o r e l eav ing t he e l i mi na t i ng

    o r gan . Fo r d r ugs l i ke the s e, w h i ch have an ex t r ac t i on r a ti o ap p r oa ch i ng 1,

    c l ea r ance is una f f ec t ed by p r o t e i n b i nd i ng , and f o r a g iven cons t an t i npu t

    R ~ C v , ~ m u s t b e t h e s a m e n o m a t t e r t h e d e g r e e o f b i n d in g c f . equat ion 6) .

    Ho we ver , now Cy,, ( and p resu m ab ly ac t iv i ty ) w ill increase dra m at ica l ly w i th

    d r ug d i s p l acem en t ( equa t i on 7).

    I n p r ac t i ce , t he s i t ua t i on can be much mor e compl i ca t ed t han t ha t

    env i s i oned du r i ng t he f o r ego i ng t heo r e ti ca l d is cuss ion . A n exce ll en t exam pl e

    is the p o te n t i a t io n of the an t i coa gu lan t e ffec t o f wa r far in in pa t i en t s r ece iv ing

    pheny l bu t azone ( 33 ) . W ar f a r i n i s ve r y h i gh l y bound t o a l bumi n and t i s s ue

    s ite s, a nd t he ph a r m aco l og i ca l e ff ect p r oba b l y is r e la t ed t o t he u nb ou nd

    c i r cu l a t i ng d r ug . Pheny l bu t azone can d i s p l ace w ar f a r i n f r om a l bumi n

    in

    v i t r o (34), and th i s d i sp lacem ent has bee n sugges ted as the cause of phen yl -

    b u t a z o n e a u g m e n t a t i o n o f w a r f a r in a c t iv i ty i n v i v o . I ndeed , w he n s ub j ec t s

    r ece i v i ng pheny l bu t azone i nges t a s i ng l e dos e o f w ar f a r i n , t he pe r cen t o f

    w ar f a r i n un bo un d i n p l a s m a inc r eas es f r om a con t r o l va l ue o f 0 .4 t o 1 .0

    (per sona l observa t ion) . Ho we ver , the e ffec ts on war far in d i spos i t ion b y

    phe ny l bu t azon e a r e f a r mo r e com pl ex (F ig . 7 ). T hes e da t a s ugges t an add i -

    t i ona l m ech an i s m f o r phe ny l bu t azon e po t en t i a t i on ( 35 ). W ar f a r i n i s ad -

    mi n i s t e r ed a s a r acemi c mi x t u r e . T he mor e po t en t i s omer i s e l i mi na t ed

    p r i ma r i l y by ox i da t i on t o 7 - hyd r oxyw ar f a r i n and is pa r ti a l ly xeduce d t o t he

    SS war far in a lcohol ( a lcohol 2 ) . The l es s po ten t R war far in i s p r imar i ly

    r educ ed t o t h e R S a l coh o l ( a lcoho l 1). P r e s en t chem i ca l a s says me as u r e t he

    s um o r S and R w ar f a r i n i n p la s ma , w h i l e t he pha r ma co l og i ca l e ff ec t p r i mar i l y

    r e f l ec t s t he S w ar f a r i n concen t r a t i on , T he dec r eas ed p r oduc t i on o f t he

    7 - hyd r oxyw ar f a r i n and i nc r eased p r od uc t i on o f t he a l coho l 1 (F ig . 7 )

    p r o m pt ed t he s ugges t ion t ha t phe ny l b u t azo ne (o r its me t abo l i te s ) mi gh t , in

    add i t i on t o d i s p l acem en t , sl ow S w ar f a r i n and has t en R w ar f a r i n (35). H e nce

    t h is i n t e r ac t i on m ay a l t e r t he i s omer i c com pos i t i on and po t en cy o f t he d r ug

    i n p la s ma , w i t hou t m a t e r i a l ly chang i ng t he t o t a l co nce n t r a t i o n - t i m e p r o fi le

    o f t he mi x t u r e .

    T h e w a r f a r i n - p h e n y l b u t a z o n e i n te r a c ti o n s t u d y s tr es se s t h e i m p o r t a n c e

    o f meas u r i ng me t abo l i t e s a s w e l l a s i n t ac t d r ug . Pha r macok i ne t i c ana l y s i s

    a i d s i n t he i n t e r p r e t a t i on o f t h is i n f o r ma t i on . A t p r es en t, one ca nno t m ode l t he

    expec t ed chem i ca l and pha r m aco l og i ca l s eque l ae r e s u lt ing f r om t h i s i n t e rac -

    t ion . Nonethe les s , i t i s hoped tha t w i th carefu l exper imenta l des ign the

    quan t i t a t i ve i n t e r r e l a t i ons h i ps can be a s ce r t a i ned . T hen , w hen cons i de r ed

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    14/15

    5 6 6 R o w l a n d a n d M a t i n

    o n t r o l

    1 0 0 0 0

    1 0 0 0 0

    P h e n y I b u t a z o n e

    T W o . 6 0 r a g .

    w - w 9 W o d i r i a

    , t - I = A lc o h ol1

    ] 2 - 2 = A lc o ho l

    Z

    ~ w 7 [ ~ - ~ - 2 7 - H v d r o x y

    t O 0 0 - 1 0 0 0

    loo loo

    g Z

    1 1

    1 1 3 4 5

    1 1 1 1 5

    d a y s d a y s

    Fig. 7 . Phenylbutazone-warfar in in teract ion in man. In th is subject , the

    to ta l p lasma war fa r in concen t ra t ion d id no t change , bu t the metabo l i te

    pattern did. Produ ction of 7-hydro xyw arfar in was depressed, but produ c-

    t ion an d el imin ation of a lcoh ol 1 were increased.

    n e c e s s a r y , a p p r o p r i a t e d o s a g e s c h e d u l e s o f t w o s u c h d r u g s i n c o m b i n a t i o n

    m a y b e p r e d i c t e d t h a t w o u l d a c h i e v e t h e d e s i r e d t h e r a p e u t i c r e s p o n s e w i t h

    m i n i m a l t o x i c i t y .

    R E F E R E N C E S

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    1969).

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    5 . K. Melmon , H. F . More l l i , J . A. Oa tes , A. H. Conney , T . N. Tozer , B. P . Harpo le , and

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