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Pharm acolog ica l Research Com municat ions , Vo l . 16, No. 7 , 1984 7 2 3

PHARMACOKINETIC STU DY ON INTRAVENOUS RIF AM PIC IN IN MAN

A c o c e l l a G . , S e g r e G .

,, . , .

, C o n t i R . , P a g a n i V . , P a l l a n z a R . , P e r n a G .

a n d S i m o n e P.

* L e p e t i t R e s e a r c h L a b o r a t o r i e s , M i l a n

* * I n s t i t u t e o f P h a r m a c o l o g y o f t h e U n i v e r s i t y , S i e n a

* * * L o c a t e l l i H o s p i t a l - G r o p p i n o ( B e r g a mo )

Recei ved m f i na l ~ r m 2F eb rua ry 1984

SUMMARY

A p h a r m a c o k i n e t i c s t u d y w a s c a r r i e d o u t i n 1 8 m a l e p a t i e n t s i n o r d e r

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

m i n i s t r a t i o n o f 3 d i f f e r e n t d o s e s ( 6 00 , 9 0 0 an d 1 20 0 m g ) o v e r 3 d i f f e -

r e n t p e r i o d s o f i n f u s i o n ( 1 , 2 a nd 3 h o u r s ) .

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

h i g h e r a n d e a r l i e r p e a k c o n c e n t r a t i o n s a r e o b t a i n e d .

A k i n e t i c a n a l y s i s b a s e d o n a o n e - c o m p a r t m e n t o p e n m o d e l g i v e s a g o o d

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

F r o m t h e s e d a t a o n e o b t a i n s f o r t he v o l u m e o f d i s t r i b u t i o n a v a l u e o f

4 8 . 1 + 1 T . 2 l i t e r s a n d f o r t h e s e r u m d i s a p p e a r a n c e r a t e th e v a l u e o f

-I0 . 2 1 2 + 0 . 0 7 0 h i n a d u l t s u b j e c t s .

I t i s p o s s i b l e t o p r e d i c t t h e t i me c o u r s e o f s e r u m k i n e t i c s o f t h e

d r u g b y u s i n g t h e e q u a t i o n

kC ( t ) = o (1 - e - 0 " 2 1 t )

2 0

(t = hour s, ko

-1= i n f u s i o n r a t e in mg h ).

0 0 3 1 - 6 9 8 9 / 8 4 / 0 7 0 7 2 3 - 1 4 / $ 0 3 . 0 0 / 0 © 1 9 8 4 T he I ta l ian Pharmacological S o c i e t y



72 4 Pharmaco~gical Resea~h Commun~ations, VoL l~ No. Z 1984

I n t r o d u c t i o n

Pre viou s stud i es have been carr ied out to assess the t ime course o¢

the serum leve ls of r i famp ic in (RAMP) in man dur i ng and af t er admi-

n ist ra t ion of doses rang ing from 150 to 600 mg by in t rave nous in f u-

s i o n ( A c o c e l l a G . e t a l . , 1 9 7 7 ; N i t t i V . e t a l . , 1 9 7 7 ) .

O f th e t h r e e m a i n v a r i a b l e s c h a r a c t e r i z i n g a n i .v . i n f u s io n , n a m e l y

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

i n f u s i o n , o n l y o n e w a s c h a n g e d i n s u c h s t u d i e s ( t h e d o s e ) , t h e o t h e r

t w o r e m a i n i n g constant ( v o l u m e = 5 0 0 m l a n d d u r a t i o n o f i n f u s i o n =

3 hours).

Under these experimental conditions the resul ts indicated that there

is a good simi lar i ty between the serum concentrations obtained after

administration of the same dose by the oral and the intravenous route,

a fact which indicated the high degree of absorption of r ifampicin

from the gast ro- in test inal tract.

The present study was undertaken in order to evaluate the pharmaco-

kinetics of RAMP when two of the three variables were modified, namely

the dose and the duration of infusion, keeping the volume of the so-

lution constant.

M a t e r i a l and Methods

1) Subjects. The study was carr ied out on a group of 18 male patients

not suffering from diseases or syndromes known or l ikely to al ter

the kinet ics of the antibi ot ic and who could benefit from the admi-

nistration o f r i f a m p i c i n . I n f o r m e d c o n s e n t w a s o b t a i n e d f r o m e v e -

ry pat ient. Each pat ient received one infusion according to the

scheme described below.

2) Treatment. Lyophi lized RAMP (300 m g and 600 mg vials) was dissolved

in the appropriate solvent (5 ml and 10 ml respect ively) and added

to a 500 ml of 5% glucose solution for phleboclysis.

A dose of 600, g00, and 1200 mg was used.



Pharm acologicel Research Com munications, Vol. 16, No. Z 1984 725

3 ) A d m i n i s t r a t i o n s c h e m e . A s s a ~ d in t h e i n t r o du c t i o n , t w o v a r i a b l e s

w e r e m o d i f i e d , t h e d o s e a n d t h e P a t e o f i n f u s i o n . T h e d o s e l e v e l s

t e s t e d w e r e 6 0 0, g 0 0 a n d 1 2 0 0 m g , e a c h d o s e b e i n g a d m i n i s t e r e d i n a

c o n s t a n t v o l u m e i n 3 h o u r s , 2 h o u r s a n d 1 h o u r .

D o s e

(mg )

6 0 0

6 0 0

6 0 0

go0go0

go0

120012001200

i u r a t i o n o f i n f u s i o n

( h )

321

3

2

1

E a c h t r e a t m e n t w a s a d m i n i s t e r e d t o 2 p a t i e n t s a n d e a c h p a t i e n t r e c e i -

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

a f f e c t e d b y p o s s i b l e c h a n g e s d u e to e f f e c t s o f s e l f - i n d u c t i o n ( A c o -

c e l l a G ., M a t t i u s s i R . , S e g r e G . , 1 9 7 8 ) .

I n a l l c a s e s , t h e i n f u s i o n w a s c a r r i e d o u t w i t h o u t t h e a id o f a r t i -

f i c i a l m e a n s o f c o n s t a n t a d m i n i s t r a t i o n 6 c o n s t a n t i n f u s i o n p u m p ) .

4 ) M e t h o d o f a s s a y . R i f a m p i c i n c o n c e n t r a t i o n s w e r e a s s a y e d i n s e r u m

w i t h t h e a g a r - p l a t e m e t h o d u s i n g S a r c i n a l u t e a A T C C 93 4 1 a s t e s t

m i c r o o r g a n i s m ( F u r e s z S. e t a l . , I g T T ) ,

5 ) K i n e t i c a n a l y s i s . F o r e a c h p a t i e n t a n d s c h e m e o f a d m i n i s t r a t i o n

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

c e n t r a t i o n d a t a a nd t h o s e c a l c u l a t e d a c c o r d i n g t o t h e e q u a t i o n

r e p o r t e d b e l o w.

F o r e a c h p a t i e n t t h e p a r a m e t e r s o f o n e - c o m p a r t m e n t o p e n m o d e l w e r e

d e t e r m i n e d f r o m t he o b s e r v e d c o n c e n t r a t i o n s , w i t h a c o n s t a n t r a t e

o f e n t r y o f t h e a n t i b i o t i c i n b l o o d ( k ) w h i c h w a s k n o w n a n d w a s d e -o

p e n d i n g on t h e a d m i n i s t r a t i o n s c h e m e . O n t h e b a s i s o f t h e s e p a r a -



7 2 6 Pharm aco log ica l Research Com mun ica t ions , VoL 16 , No. 7 , f 98 4

n le te rs , a f i t t i n g o f t h e e x p e r i m e n t a l d a t a w a s p e r f o r m e d f o r e a c h

case,

The blood samples were taken at t ime O, and then at 10; 30; 60; 90

m i n u t e s , a n d 2 ; 4 ; 8 h o u r s f r o m t h e b e g i n n i n g o f t h e i n f u s i o n .

The m a t h e m a t i c a l m o d e l i s

dC/dt = -K C + k /V for 0 4 t 4 T (duri ng the infu sion )o

d C / d t = - K C f o r t ~ T ( a f t e r t h e i n f u s i o n )

( C = s e r u m c o n c e n t r a t i o n o f R A M P ( ~ g : m l ) ; t = t i m e i n h o u r s ; T = i n f u -

s i o n t i m e ; V = v o l u m e o f d i s t r i b u t i o n i n m l ; K = e l i m i n a t x o n c o n s t a n t ;

-1k = Dos e/T = inf usi on rate, in mg h ).o

T h e s o l u t i o n o f t h i s m o d e l i s g i v e n b y t h e e q u a t i o n s :

ko

C : (I - e -Kt) for 0 ~ t ~ T (1)

V . K

a n d

ko

-KT -K(t - T) -K(t -T)C = (1 - e ) e = C(T) e for t~ T ( I I )

V.K

The asymptoti c value of C can be cal cu lat ed to be:

ko

c( ~ ) . . . . . . . (zzz)

V . K

i n th i s c a s e ( w h e n t h e i n f u s i o n i s c a r r i e d o u t f o r a n e n o u g h l o n g t i m e )

a steady state i s reached from which one obtains

k = C ( o . , : ~ ) . V.K ( I V )o

T h e v a l u e o f V c a n b e c a l c u l a t e d f r o m e q . ( I V ) , b e i n g V =

f r o m t h e e q u a t i o n

V . K °

ko

or

C ( c ~ c m ) , KD o s e

= C l e a r a n c e , b y n ot i n g t h a t: C l e a r a n c e =

C . d t

o

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

t e c h i n i q u e s a n d t h e S A A M - 2 7 p r o g r a m ( B e r m a n M . , W e i s s M . F. , 1 9 7 4) .



Pha rmac o log ica l Research Com mu nica t ions . Vo l . 16 , No, 7 , 1984 727

6 . T o l e r a n c e . I n a l l p a t i e n t s l o c a l t o l e r a n c e t o t h e i n f u s i o n w a s e v a l u a t ed .

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

c o m p l e t i o n , a n d 2 h o u r s a f t e r t h e e n d o f t h e i n f u s i o n .

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

f o r a n t i b i o t i c a s s ay .

R E S U L T S

K i n e t i c s o f r i f a m p i c i n i n b l o o d .

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

t e r v a l s w i t h t he 9 d i f f e r e n t a d m i n i s t r a t i o n s c h e m e s i n 1 8 s u b j e c t s .

W i t h i n e a c h g r ou p , i f t h e r a t e o f i n f u s i o n i s i h c r e a s e d , a n i n c r e a s e o f t h e

p e a k v a l u e s i s o b s e r v e d w h e n t h e h i g h e s t d o s e w a s i n f u s e d f o r I h o u r .

I n T a b l e I I t h e va l u e s o f th e p a r a m e t e r s c a l c u l a t e d f o r e a c h s u b j e c t a r e

s h o w n , t h e m e a n v a l u e o f K ( e l i m i n a t i o n c o n s t a n t ) i s 0 . 2 1 2 h - I ( w i t h a

m e a n h a l f - l i f e o f 3 . 2 7 h o u r s ) a n d t h a t o f V ( v o l u me o f d i s t r i b u t i o n ) i s

4 8 . 1 4 L ; t h e i r c o e f f i c i e n t o f v a r i a t i o n i s 3 2 . 8 % a n d 3 5 . 7 % r e s p e c t i v e l y .

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

o r d u r a t i o n o f t h e i n f u s i o n .

T h e m e a n v a l u e o f K c o r r e s p o n d s t o t h e s u m of th e o u t f l o w t r a n s f e r c o n -

s t a n t s f r o m t h e c e n t r a l c o m p a r t m e n t o b t a i n e d i n a p r e v i o u s s t u d y ( A c o-

c e l l a G. , M a t t i u s s i R ., S e g r e G . , I g 7 8 ) o f s e r u m k i n e t i c s o f R A M P a f t e r

-Io r a l a d m i n i s t r a t i o n f r o m w h i c h th e v a l u e o f 0 . 2 3 6 h i s o b t a i n e d a n d

w h i c h i s m a i n l y d u e t o t he b i o t r a n s f o r m a t i o n o f R A M P i n t o d e s a c e t y l - R A M P

-I(O.22 1 + o.ogo h ).

-

The values of AUC ~ C.dt calculated by the trapezoidal method areO

shown in Table I I I .

I t is evident that the values of AUC for the 2 cases in which 1200 mg

of RAMP were infused in I hour are quite er ratic with respect to the other

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

I t c a n b e a s s u m e d t h a t i n t h es e 2 c a s e s t h e k i n e t i c s a p p r o a c h e s a s a t u r a -

t i o n p h e n o m e n o n .



T

E

-S

MRF

M

CNLE

S~

m

O

ATH

N

C

TM

N

SD

N

A

A

A

Y

IN

U

O

OD

F

D

O

DF

N

U

O

TM

D

D (mg

600

600

600 9 90

0 900

D

O

O

TH

INU

O

(h

s2

S

EN

-

_

.

.

_

.

9

2 I

S

MRF

M

CNLE

SA

TH

N

C

TM

FR

TH

BGN

N

O

TH

IN

U

O

TOmn

30 mn

Ih

0.80

2.10

3.89

0.92

10

2.33

lJ

2

4h

8h

5.95

7.06

6.29

2.8I

3.98

3.64

6.04

3.56

IZ

1.87

3.39

5.96

9.39

5.73

l

1.68

1.97

3.49

6.41

1.70

2.24

0.27

51

I04

1

8

57

I

9

1

9

I2

2.58

4.33

1.40

2.2

4.52

1.31

2.47

I0

4.58

8.54

I

8.87

I9.79

I2

7.28

19

I2.20

I0.48

8.85

3.59

I2.05

I48

7.48

1.54

6.01

6.7~

6,72

3.59

6.44

9.20

8.01

42

6.9

9.55

I2.84

9.82

5.14

I63

I6.72

I6.77

8.71

3.25

20.94

I6.65

I4.89

9.67

3.70

I3.87

I2.99

20.09

14.58

8.37

I

!

-

-

--

-

"

-

[

~

.

.

.

.

.

.

.

-

-

.

.

.

.

-

-

-

-

-

-

.

-

.

~

_

_

-

I3

1.60

2.8I

6.92

I70

14.32

11.76

5.25

I200

3

I4

5,47

7.55

I4.3

17,34

2.3

I7.87

I95

I200

2

1L

I5

1 I7

I8

2.46

4.06

9.06

I2.57

I3.62

8,65

4.73

3.27

4.89

I23

14.65

I5.89

I6

5.18

10.42

24.93

31.13

19.94

18.40

23,45

I0.85

9.52

19.9I

38.42

26.63

25.02

23.57

I3.27

L

,o ,z

~



Kn

cp

ameescm

e

n

1

s

e

s

Q}

Su N

,1 2 3 4 5 6 7 8 9

1 1 1 1 1 1 1 1 1Mean

s.d.

(mg

ko -

1

h 2 2 3

O

3 6 6 3O0

3 4 4 9 9 4 4 6O0

61 1

T

D

(mg

ko

K

(k

T

C(q

w~

~

-1

(h

o

(h

(u

mi)

3

6

3

6

2

6

2

6

1

6

1

6

3

9

3

gO0

2

9

2

gO0

1

go0

1

9

V (L)

CIDo

A

C}

(mlh

3

1

3

1

2

1

2

1

1

1

1

1

1

4

0

2

4

5

1

7

2

2

0

1

6

8

1

0

2

4

0

1

6

4

1

0

7

1

0

3

1

5

32

8

4

0

2

3

5

7

5

5

8

0

3

3

0

g

g

1

4

0

2

7

o

1

1

2

2

0

2

6

8

1

3

5

9

0

1

7

0

8

5

4

4

0

2

3

3

1

5

g

0

0

2

3

6

9

6

1

0

0

2

4

8

6

1

3

3

0

2

5

6

1

2

6

8

0

2

3

8

5

9

4

7

0

1

7

6

1

2

5

0

0

1

5

5

1

1

2

0

0

1

4

2

5

1

2

8

0

1

3

7

4

4

0

2

4

1

g

g

0

0

1

1

3

0

5"

{b F, .o



7 3 0 P h a r m a c o /o g i c a / R e s e a r c h C o m m u n i c a t i o n s , V o t 1 6, N o 7 , 1 9 8 4

T A B L E III

V a l u e s o f t h e A u c B ( m g / m l / h ) f o r th e v a r i o u s d o s e s a n do

d u r a t i o n s o f i n f u s i o n o f r i f a m p i ci n .

D o s e(m g )

D u r a t i o n o f i n f u s i o n (h)m e a n A U C + s . d .

1 2 3

600 7 9 . 1 4 9 . 7 5 1 . 05 2 . 7 0 + + 2 0 . 7 8

6 0 , 6 1 6 . 1 5 9 . 7

900 9 3 . 3 1 0 5 . 7 5 g . 39 2 . 4 3 + 3 0 . 5 7

1 4 5 . 4 7 9 . 2 7 2 , 7

1 2 0 0 2 3 1 . 4 " 9 0 . 4 9 7 . 8

1 6 6 . 0 8 + 7 7 . 1 32 6 7 . 9 * 1 0 7 . 3 2 0 1 . 7 1 2 4 . 3 0 ; 5 2 . 0 6 " *

* * v al u e c a l c u l a t e d o m i t t i n g *

k •

F i g . I - P l o t o f k • v s C |= )

]OOO

5 0 0 1 •o • •

2o

Q @ Q •

0 0

• , I I I '

4 'o 8 b 1 6 o c l = )

@ @

I f t h e s e 2 c a s e s a r e e x c l u d e d o n e o b t a i n s f o p t h e r e g r e s s i o n b e tw e e n

A U C ( y) a n d t h e d o s e ( x) t h e e q u a t i o n :

y = - 1 8 . 2 7 + 0.1 20 x (r = 0.677; P ~ 0.01).



Pharmaco~g~alResea~hCommunmations, VoL 1~ No. Z 1984

T h e v a l u e s o f t h e t o t a l b o d y c l e a r a n c e c a l c u l a t e d f r o m t he f o r m u l a : d o s e /

A U C a p e s h o w n i n T a b l e I ~ t h o i r m e a n v a l u e i s e q u a l t o a b o u t 1 0 m l / h .

A p l o t o f k v s C ( ~ ) ( s e e T a b . I I ) s h o w s ( f i g. I ) t h a t , i f t h e t w oo

v a l u e s o f C ( ~ ) f o p k e q u a l t o 1 2 0 0 a r e e l i m i n a t e d , t h e o t h e r va l u e so

c a n f i t a s t r a i g h t l i n e :

C (o- ~) : 0.185 + 0.108 . k ( r = 0.8 44; P < 0.0 01)o

w h e r e a s t h e p r e v i o u s t w o v a l u e s a r e n o t a l o n g t he s t r a i g h t l i n e; t h e r e f o r e

-1i t a p p e a r s t h a t a t a n i n f u s i o n P a t e o f 1 2 0 0 m g h t h e e l i m i n a t i o n p r o -

c e s s i s n o m o p e l i n e a r ; i n f a c t at a c l o s e r e x a m i n a t i o n o f t h e s e r u m

k i n e t i c s o f t h e s e t w o s u b j e c t s ( N o. 1 7 a n d 1 8 ) i t i s d i f f i c u l t t o a s c e r -

t a i n w h e t h e r i t f o l l o w s a z e r o o r a f i r s t o r d e r .

731

To l e r anc e

For a l l the admin i s t ra t i on schemes inves t i ga te d the l oca l to le r ance was

en t i r e l y s a t i s fac to r y .

The serum to ta l b i l i ru b in l eve ls ape repo r ted i n Tab le IV .

As expe cted on the b as i s of the i nte rac t io n between RAMP and bi l i ru bin

which compete w i th each o the r fop b i l i a r y exc re t i on (Acoce l l a G. , Mat -

t i uss i R. , Tencon i L .T . , 1973) , a cer ta in i nc re ase o f the serum b i l i -

rub in l eve ls was obser ved.

As a resu l t o f compe t i t i on , RAMP i s pre f erent ia l l y exc re t ed, th i s s lo w-

ing down the t ran s fer o f b i l i ru b in th rou gh the l i ver ; i n consequence the

s er um to ta l b i l i r ub i n c onc en t r a t i ons i nc r eas e .

The inc re ase was o f l i t t l e , i f any , re leva nce in the sub je c ts rece i v ing

the 600 mg dose and the g00 mg dose in thr ee hou rs, the lev els being in

these cases w i th i n the normal range.

Lev els somewhat hig her than the upper l imi t of norma l i t y (1 mg/100 ml

serum) were found to be ass oc i ate d wi t h th e admin is t r at i on of 900 mg in

I hour and of 1200 mg in 2 and I hour.

In agreement w i th prev ious dat a on i . v . i n fus ion o f r i fam yc in SV (Aco-

cel la G., Nicol is F.B .~e nco ni L.T . , 1965) the phenomenon was mope marked

a t t he h i ghe r r a te o f adm i n i s t r a t i on .

W i t h r i f a m y c i n S V a n d r i f a m y c i n M 1 4 ( A c o c e l l a G ., N i c o l i s F . 8 . , T e n c o n i



73 2 Pharmacological Reseat,oh Com mu nications, VoL 16. No. 7 , 1984

TABLE IV

S e r u m b i l i r u b i n l e v e l s ( m g / 1 0 0 ml ) a t d i f fe r e nt ; t i m e i n t e r v a l s

d u r i n g a n d a f t e r a n i. v. i n f u s i o n o f r i f a m p i c i n a t d i f f e r e n t

doses over a di f ferent period of infusion.

DOSe (~ )

600

600

~0

900

900

1200

1200

DURATION

OK T~E

INFUSION

1

5

2

1200

su~e~ No.

1

2

3

5

6

7

8

0

0.38

0.36

0.59

0.22

O.q8

0.58

0.43

0.$6

, , ~ , _ , , _ - .

SERUM tlL IRUI lIN LEVELS

~tN ~ a 8 .

4),~ 0.7O 0.86

{I,,65 0,81 0.

0.~ 0,62 O.54

0.59 0.~3 0.~2

0.S~ 0.65 0,58

0.~ 0.~ 0.~6

0 . 5 ~ 0 . 9 7 0 . 8 1

0 , 6 5 0 . 7 8 0 . ~

9

10

11

12

0.22 C.65 0.76 0.58

0,59 0.97 1.41 1.0~

0.28 0.97 0.76 0.B5

0 .~ 0.81 0.97 0.75

0.54 0.65 0.83 0.65

0 , ~ 0.76 0.97 0.9"2,, ,

1 5

1 6

1 7

1 8

0.36 0,97

0 , 5 4 0 . 7 6

0 . 2 8 1 . 2 8

0.36 0.~

l . l q 1 . 0 3

0.97 0.75i , , , ,

I . 0 O , 76

0 . 9 9 1 . 0 8

L.T. , 1965; Acocella G. et al . , 1966) and with oral ri fampicin (Acocella

G., Matt iuss i R., Te nconi L .T. , 1973) the increa se was found to be tran -

s i e n t , t h e b i l i r u b i n l e v e l s r e t u n n i n g w i t h i n n o r m a l l i m i t s a few hours

after stopping the infusion.

The comparison of the 8th versus 4th hours values and the levels at the

1 2 t h h o u r i n s u b j e c t s N o . 1 7 a n d 1 8, s t r o n g l y s u g g e s t s t h a t a s i m i l a r s i -

tuation occurs with i.v. RAMP,



Pharmacological Research Comm unicat(ons, V o l . 1 6 , No. 7, 1984 733

TABLE V - MAXIMAL AND MINIMAL BLOOD PRESSURE VALUES RECORDED AT THE BEGINNING, AT THE END AND

2 HOURS AFTER THE END OF THE INFUSION OF DIFFERENT DOSES OF RIFAMPICIN

DOSE (MG)

600

600

600

900

900

DURATION

OF THEINFUSION

(HOURS)

3

2

1

SUBJECT No.

1 4 5 / 8 5

i05180

135/60

115150

MAXIMALAND MINIMAL BLOODPRESSURE

END OF THE

INFUSION

1 4 0 1 8 0

I00175

145170

I05155

2 H AFTER THEEND

OFTHE INFUSION

145/90

i00175

135170

115160

900 1

1 2 0 0

1200

1 2 0 0

9

i 0

11

12

13

14

1 5

16

17

18

1 6 0 1 8 5

i 1 5 1 7 5

130/90130170

110/60

115/80

1 4 0 1 7 0

1 4 0 1 8 5

1 2 0 / 8 0

1 5 0 / 8 0

140/80

. I , I O 5 1 5 5

1 1 5 / 7 5

140/80

145/g0

115170

120/80135/80

105170

125/80

1 3 0 / 8 0

1 5 0 / 1 0 0

1 3 0 / 8 0

1 4 5 1 9 5

120/80

120170

105175

140/70

1 6 0 / 9 5

1 1 5 / 7 0

1 2 0 / 8 0

1 2 5 / 7 0

100/60

125/90

1 4 5 / 8 0

1 5 0 / 9 5

130/80

140/85

1 4 0 / 8 0

1 0 0 / 7 0

120180

150/90

The values of &rt er ial blood pressure recorded before, on completion

and 2 hours &f ief the end of the i nf us ion have shown a sl ight increase or

decre&se in the values which seem comp&tible wi th the normal v&r iat ion

inherent in the measurement process (+ 10 mm Hg) (Table V ).

DISCUSSION AND CONCLUSIONS

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

r i f a m p i c i n f r o m 5 0 0 t o 1 2 0 0 m g a n d b y r e d u c i n g t h e d u r a t i o n o f i n f u s i o n

f r o m 3 t o I : : ou r a t c o n s t a n t v o l u m e a l i n e a r i n c r e a s e i n s e r u m a s y m p t o t i c



7 3 4 Pharmacological ~esearch Commun~atlon~, VoL 16 No. ~-1984

c o n c e n t r a t i o n , C ( ( > q ) ) , i s o b t a i n e d f o r i n f u s i o n r a t e s f r o m 2 0 0 to g O 0

-1mg h .

-1A b o v e t h i s ra t e ( at 1 2 0 0 m g h ), t h e v a l u e s of C ( ~ ) s h o w a d e p a r t u r e

f r o m l i n e a r i t y ; t h i s f a c t p o i n t s t o a s a t u r a t i o n k i n e t i c s i n t he e l i m i n a -

t i o n p r o c e s s w h e n s e r u m l e v e l s o f R A M P r e a c h a n d e x c e e d a g i v e n v a l u e

(between 2 5 an d 3 0 u g / m l ) .

F o r t h e sam e r a n g e o f a d m i n i s t r a t i o n s c h em e s , a c l o s e c o r r e s p o n d e n c e

b e t w e e n t h e e x p e r i m e n t a l c u r v e a n d t h a t c a l c u l a t e d on the b a s i s o f a

o n e - c o m p a r t m e n t o p e n m o d e l w a s f o u nd .

T h e k i n e t i c a n a l y s i s h a s p r o v i d e d e v i d e n c e t h at t he n u m e r i c a l v a l u e o f

t h e s u m of t he 3 b as i c t r a n s f e r c o n s t a n t s g o v e r n i n g t h e p r o c e s s o f di -

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

t h e or a l a n d fo r t he i . v. a d m i n i s t r a t i o n ( A c o c e l l a G ., M a t t i u s s i R .

an d S e g r e G . , 1 g 7 8 ) .

T h i s r e s u i t i s o f p a r t i c u l a r r e l e v a n c e s i n c e . t h e t wo c o n d i t i o n s a r e r e -

m a r k a b l y d i f f e r e n t , t h e f i r s t i n v o l v i n g t h e e x i s t e n c e o f a v e r y i m p o r -

t a n t ( f o r r i f a m p i c i n ) f i r s t - p a s s e f f e c t t h r o u g h t h e l i v e r ; w h e re a s t h e

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

d i r e c t l y t h e c e n t r a l ( b l o o d ) c o m p a r t m e n t .

F u r t h e r s t u d i e s a r e n e ed e d t o c l a r i f y t h e m e c ha n is m u n d e r l y i n g t h e s a t u -

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

A c o m p a r a t i v e s t u d y on t h e b i l i a r y e x c r e t i o n o f t h e d r u g i n v a r i o u s c o n -

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

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

u s e , t h e k i n e t i c p r o p e r t i e s o f i. v . r i f a m p i c i n s e em p a r t i c u l a r l y e n c o u r a -

g i n g . T h e ; ' p r e d i c t a b i l i t y " o f t h e m a g n i t u d e o f t h e p e a k c o n c e n t r a t i o n

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

h a s in m i n d t h e t r e a t m e n t o f s e v e r e c a s e s w h e r e , f o r e x a m p l e , o r a l a d m i n i -

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

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

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

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

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



PharrnacologicalResear~h Com mun ications, VoL 16 N o. ~ 1984

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

B y u s i n g t h e ~ q u a t i o n ( I) a n d t h e m e a n V a l u e s f o r K a n d f o r t h e p r o d u c t

K . V o b t a i n e d f r o m T a b l e I I o n e g et s

k

C(t ) = o (1 - e- O'21 t) . (V)

20

735

By su bs t it ut in g k wit h the real value (u nt il go0 mg) one can approximateo

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

t h e i n f u s i o n .

B y u s i n g e q u a t i o n ( V) o n e o b t a i n s f o r C ( t ) v a l u e s s o m e w h a t h i g h e r t h a n

t h o s e f o u n d e x p e r i m e n t a l l y i n T a b l e I f o r l o w e r v a l u e s o f k ( 2 0 0 a n do

3 0 0 ) a n d v a l u e s s o m e w h a t l o w e r f o r h i g h e r v a l u e s o f k f o r an i n f u s i o no

o f 2 h o u r s .

I t s h o u l d h o w e v e r b e o b s e r v e d ~ h a t t h e v a r i a b i l i t y o f t h e e x p e r i m e n t a l

d a t a ( c a l c u l a t e d f o r k = 3 0 0, f o~ " w h i c h v a l u e 4 e x p e r i m e n t s a r e a v a i l b l e )o

c o r r e s p o n d s t o a c o e f f i c i e n t o f v a r i a t i o n o f a b o u t 22 % .

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

s e r u m l e v e l s o f a b o u t 1 0 m c g / m l ) s h o u l d b e a p r i m i n g i . v, d o s e o f 0 . 5 g

o f r i f a m p i c i n a n d i n f u s e a t t h e s a m e t i m e t h e ~ r u g a t a rate ( k ) o f

-1 o

1 0 0 m g h .

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

a n d s i nc e t h e t r a n s f e r f r o m ' t h e G . I . t r a c t t o c i r c u l a t o r y b l o o d r e q u i r e s

o n e s t e p o n l y ( A c o c e l l a G . , M a t t i u s s i R ., S e g r e G ., 1 9 7 8 ) , n o d i f f e r e n c e s

o f r e l e v a n c e b e t w e e n s e r u m l e v e l s a f t e r o r a l a n d i . v. a d m i n i s t r a t i o n o f

t h e s a m e d o s e a r e o b s e r v e d .

A f u r t h e r e l e m e n t i n c o m m o n b e t w e e n t h e o r a l a n d t h e i . v. u s e o f r i f a m p i -

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

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

k n o w l e d g e o n n i f a m y c i n s .

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

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

I n s o m e r e s p e c t , a s w i t h o t h e r a n t i b i o t i c s , t h e i. v . r o u t e s e e m s t o



736 Pharm aco~g ica /Rese s~hC omm un~at ions , VoL 1~ No. Z 1984

prese nt some advan tage in compar ison to the oral route, a fact which can

f i n d i t s m o s t u s e f u I a p p l i c a t i o n i n s e l e c t e d c l i n i c a i c a s e s .

R E F E R E N C E S

1 ) A C O C E L L A G ., N I C O L I S F . 8 ., a n d T E N C O N I L . T . ( 1 96 5 ). G a s t r o e n t e r o l o g y

4g, 521-25

2) ACOCELLA G. et a l . (1 965 ). Gut ~, 380-86.

3) ACOCELLA G. , MATTIUSSI R ., and TENCONI L.T. ( 1973). Ti jd sc hr if t voor

Gastr o -Ent ero lo g ie 16 , 186-190.

4) ACOCELLA G. et al. (1977). Ar zn ei mi tt el -F or sc hu ng 27, 1221-26.

5) ACOCELLA G., MATTIUSSI R., and SEGRE G. (1 978 ). Ph ar ma co lo gi ca l

Research Communications 10, 271-88.

6) BERMAN M., WEISS M.F. (1 974 ). SAAM 27 Manual, La bo ra to ry of The or e-

t i c a l B i o l o gy , N a t i o n a l C a n c e r I n s t i t u t e, N a t i o n a l I n s t i t u t e of

Health, Bethesda, Maryland.

7) FURESZ S. et a l . (1977). Arz nei mit te l -Fo rsc hun g 17, 726-35.

8) NITTI V. et al. (1977 ). Chemotherapy 23, 1-6.

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