Europ. J.clin. Pharmacol. 9, 439-441 (1976) © by Springer-Verlag 1976
The Influence of Disulfiram on the Half Life and Metabolic Clearance Rate of Diphenylhydantoin and Tolbutamide in Man T. Lysbo Svendsen, M. Brandt Kristensen, J. M¢lholm Hansen and L. Skovsted M e d i c a l Dept. C, D i a k o n i s s e s t i f t e l s e n , Copenhagen, Denmark
Received: accepted:
M a r c h 4, 1975, and in r e v i s e d S e p t e m b e r 3, 1975
and M e d i c a l
form:
Dept.
August
25,
F, G e n t o f t e H o s p i t a l ,
1975,
Summary.
D i p h e n y l h y d a n t o i n (DPH) and t o l b u t a m i d e serum levels were s t u d i e d in ten v o l u n t e e r s b e f o r e and a f t e r 4 days of d i s u l f i r a m treatment. The m e a n DPH half life i n c r e s e d s i g n i f i c a n t l y from 11.0 ± 1.2 h to 19.O ± 3.3 h, and the m e a n DPH m e t a b o l i c c l e a r a n c e rate d e c r e a s e d s i g n i f i c a n t l y from 51.2 ± 17.2 m l / m i n to 33.9 ± 12.O m l / m i n d u r i n g m e d i c a t i o n . No s i g n i f i c a n t c h a n g e s in the half life or m e t a b o l i c c l e a r a n c e rate of t o l b u t a m i d e was observed. Tolbutamide, s e r u m level.
Key words:
rate,
diphenylhydantoin,
In 1966 O l e s e n s h o w e d that a d m i n i s t r a tion of d i s u l f i r a m to p a t i e n t s on d i p h e n y l h y d a n t o i n (DPH) t r e a t m e n t res u l t e d in an i n c r e a s e d c o n c e n t r a t i o n of DPH in serum. The rise in s e r u m DPH was o b s e r v e d as early as four hours a f t e r i n g e s t i o n of d i s u l f i r a m . Later, he found a d e c r e a s e in the m e a n e x c r e t i o n of p a r a h y d r o x y - d i p h e n y l h y d a n t o i n (HPPH) (5-(p-hydroxyphenyl)-5-phenylhydantoin in urine d u r i n g a d m i n i s t r a t i o n of d i s u l f i r a m to D P H - t r e a t e d p a t i e n t s (Olesen, 1967). F r o m these f i n d i n g s he s u g g e s t e d that d i s u l f i r a m i n h i b i t e d the p a r a h y d r o x y l a t i o n of DPH, a p r o c e s s known to take place in the drug m e t a b o l i z i n g e n z y m e s y s t e m of the liver. The i n h i b i t i n g e f f e c t of d i s u l f i r a m on drug m e t a b o l i s m was later c o n f i r m e d by R o t h s t e i n (1968) and E l l i o t et al. (1971), w h o found an i n c r e a s e in the h a l f - l i f e of w a r f a r i n and antipyrin, respectively, after disulfiram treatment. The aim of the p r e s e n t i n v e s t i g a tion was to study w h e t h e r d i s u l f i r a m w o u l d also i n h i b i t the m e t a b o l i s m of t o l b u t a m i d e , w h i c h seemed of i n t e r e s t both from a t h e o r e t i c a l and a c l i n i c a l p o i n t of view.
drug
interaction,
disulfiram,
clearance
M A T E R I A L AND M E T H O D S Ten v o l u n t e e r s (2 females and 8 males, aged 22-72 yrs) were studied. The subjects did not r e c e i v e any drugs for at least one w e e k p r i o r to the study and none had any signs of renal or h e p a t i c disease. The h a l f - l i f e (T~) of t o l b u t a m i d e was d e t e r m i n e d by m e a s u r i n g its serum c o n c e n t r a t i o n 1.5, 3, 4.5, and 6 hours a f t e r i n t r a v e n o u s i n j e c t i o n of 500 mg t o l b u t a m i d e . The serum t o l b u t a m i d e conc e n t r a t i o n was d e t e r m i n e d by the m e t h o d d e s c r i b e d by S p i n g l e r (1957). The halflife was d e t e r m i n e d from these v a l u e s p l o t t e d a g a i n s t time on s e m i l o g a r i t h m i c paper. The h a l f - l i f e of DPH was d e t e r m i n e d after 100 mg of the drug l a b e l l e d w i t h 20 m i c r o c u r i e 14C I had been g i v e n intravenously. B l o o d samples were c o l l e c t e d 3, 6, 9 and 12 hours after the injection. DPH was e x t r a c t e d as d e s c r i b e d p r e v i o u s l y (Hansen et al., 1968). The r a d i o a c t i v i t y of the e x t r a c t s was p l o t -
l 5,5 diphenylhydantoin (4-14C) N.E.N.
440
ted against time on semilogarithmic p a p e r in o r d e r to d e t e r m i n e t h e h a l f life. T h e d i s t r i b u t i o n v o l u m e of t o l butamide and DPH was determined from the dose given and the concentration in serum at zero time found by extrapolat i o n of t h e h a l f - l i f e c u r v e . M e t a b o l i c c l e a r a n c e r a t e w a s c a l c u l a t e d as V D • In 2/T~. The half-life of both drugs was det e r m i n e d b e f o r e a n d a f t e r t r e a t m e n t for 4 days with disulfiram, which was given o r a l l y in the f o l l o w i n g d o s e s : Ist d a y 4 0 0 m g t h r e e t i m e s , 2 n d d a y 4 0 0 mg, a n d 3 r d a n d 4 t h d a y s 2 0 0 m g p e r day.
D P H of 73% a n d a d e c r e a s e in its m e a n m e t a b o l i c c l e a r a n c e r a t e of 34% w a s found after the disulfiram treatment. These changes were statistically s i g n i f i c a n t . T h e r e w a s no s i g n i f i c a n t a l t e r a t i o n in t h e d i s t r i b u t i o n volume of DPH. N o s i g n i f i c a n t c h a n g e s a f t e r d i s u l f i r a m t r e a t m e n t w e r e o b s e r v e d in a n y of t h e p a r a m e t e r s o f t o l b u t a m i d e metabolism studied.
DISCUSSION
RESULTS The results An increase
a r e g i v e n in T a b l e s I a n d in t h e m e a n h a l f - l i f e o f
2.
The finding that disulfiram increased the half-life and decreased the metab o l i c c l e a r a n c e r a t e of D P H w a s in a c c o r d a n c e w i t h t h e r e s u l t s of O l e s e n (1966, 1967), a n d s u g g e s t s t h a t disu!firam inhibits the hepatic metabo-
Table I. Pharmaeokinetic parameters of diphenylhydantoin before and during treatment with disulfiram Patient NO.
Half-life (hours)
Distribution (litre)
volume
Metabolic clearance rate (ml/min)
be fore
during
be fore
during
be fore
during
1
12.0
13.8
40.0
35.0
38.2
29.1
2
9.5
19.6
47.0
66.0
57.0
38.7
3
i0.0
21.8
32.0
39.O
36.2
20.6
4
12.3
18.O
84.O
81.O
78.4
52.1
5
ii .2
21.7
45.0
55.0
46.3
29.1
li.O ± 1.2
]9.0 -+ 3.3
49.6 -+ 20.0
55.2 + 19.O
51.2 _+ 17.2
33.9 ± 12.O
Mean value ± SD
0.01 < p < 0.02
N.S.
0.O01 < p < O.O1
Table 2. Pharmacokinetic parameters of tolbutamide before and during treatment with disulfiram Patient No.
Half-life (hours)
Distribution volume (litres)
Metabolic clearance rate (ml/min)
before
during
before
during
before
during
6
5 .O
5 .O
7
4.5
5.O
8
6.0
6.0
6.9
6.7
13.O
12.9
9
5.3
5.0
6.7
6.4
14.1
15.4
iO
5.5
5.8
6.7
6.7
14.0
13.4
5.2 ± 0.6
5.4 ± 0.5
6.8 a
6.6 a
13.7 a
13.9 a
Mean value ± SD a
Mean of 3 patients
441
l i s m of DPH. D P H is h y d r o x y l a t e d to H P P H w h i c h is e x c r e t e d by t h e k i d n e y s after glucuronidation. It is k n o w n t h a t t h i s p a r a h y d r o x y l a t i o n t a k e s p l a c e in t h e m i c r o s o m a l e n z y m e s y s t e m of t h e l i v e r in a n i m a l s as w e l l as in m a n . Tolbutamide is o x i d i z e d in t h e l i v e r to h y d r o x y m e t h y l t o l b u t a m i d e and carboxytolbutamide ( B ~ n d e r et al., 1956). T h i s p r o c e s s , too, t a k e s p l a c e in t h e microsomal e n z y m e s y s t e m in a n i m a l s a n d p r o b a b l y a l s o in m a n b u t d i r e c t e v i d e n c e of t h i s is l a c k i n g . A n u m b e r of d r u g s h a v e b e e n s h o w n to i n h i b i t t h e m e t a b o l i s m b o t h of D P H and tolbutamide in m a n , e.g. d i c o u m a r o l ( H a n s e n et al., 1966; K r i s t e n s e n et al., 1967), s u l f a p h e n a z o l e (Skovsted et al., 1974; C h r i s t e n s e n et al., 1963) , s u l f a methizole ( L u m h o l t z et al. 1975), oxyphenbutazone ( S k o v s t e d et al., 1974; Kristensen and Christensen, 1969), c h l o r amphenicol (Christensen and Skovsted, 1969), a n d c l o f i b r a t e ( S k o v s t e d et ai.1974). In v i e w of t h e s e s t u d i e s i t is s u r prising that disulfiram, as s h o w n here, d i d n o t i n f l u e n c e the m e t a b o l i s m of tolbutamide. A possible explanation c o u l d be t h a t d i s u l f i r a m is a m o r e s p e c i f i c i n h i b i t o r of t h e m i c r o s o m a l enzyme system than the other drugs mentioned above. If d i s u l f i r a m w e r e to i n h i b i t t h e metabolism of D P H c o m p e t i t i v e l y , a further possible explanation of t h e d i s crepancy might be that tolbutamide was g i v e n in a m u c h l a r g e r d o s e t h a n DPH. If t h i s w e r e c o r r e c t , it m i g h t b e e x pected that disulfiram would prolong t h e h a l f - l i f e of t o l b u t a m i d e g i v e n in a s m a l l e r dose. T h i s s u g g e s t i o n is b e i n g s t u d i e d at p r e s e n t . It is k n o w n t h a t d i s u l f i r a m g i v e n to p a t i e n t s t r e a t e d w i t h D P H c a n l e a d to DPH intoxication (Olesen, 1966). As it was impossible to s h o w an e f f e c t of disulfiram on tolbutamide metabolism t h e r e s e e m s no r i s k of a c c u m u l a t i o n of tolbutamide after administration of disulfiram.
REFERENCES B~nder, A., Scholz, J.: Tierexperimentelle Untersuchungen. Spezielle pharmakologische Untersuchungen mit D 860. Dtsch. med. Wschr. 81, 889-891 (1956)
Christensen, L.K., Hansen, J.M., Kristensen, M.: Sulphaphenazole induced hypoglycaemic attacks in tolbutamide-treated diabetics. Lancet 1963 II, 1298-1301 Christensen, L.K., Skovsted, L.: Inhibition of drug metabolism by chloramphenicol. Lancet 1969 II, 1397-1399 Elliot, S.V., Pasananti, G.T., Lee, C.H.: Impairment of drug metabolism by disulfiram in man. Clin. Pharmacol. Ther. 12, 785-792 (1971) Hansen, J.M., Kristensen, M., Skovsted, i., Christensen, L.K.: Dicoumarol-induced diphenylhydantoin intoxication. Lancet 1966 I L 265-266 Hansen, J.M., Kristensen, M., Skovsted, L.: Sulthiam (Ospolot ®) as inhibitor of diphenylhydantoin metabolism. Epilepsia 9, 17-22 (1968) Kristensen, M., Hansen, J.M.: Potentiation of the tolbutamide effect by dicoumarol. Diabetes 16, 211-214 (1967) Kristensen, M., Christensen, L.K.: Drug induced changes of the blood glucose lowering effect of oral hypoglycemic agents. Acta diabet. lat. VI (Suppl. i), 116-136 (1969) Lumholtz, B., Siersbaek Nielsen, K., Skovsted, L., Kampmann, J., Hansen, J.M.: Sulfamethizole induced inhibition of diphenylhydantoin, tolbutamide, and warfarin metabolism in man. Clin. Pharmacoi. Ther. 17, 731-734 (1975) Olesen, O.V.: Disulfiram (Antabuse ®) as inhibitor of phenytoin metabolism. Acta pharmacol. (Kbh.) 24, 317-322 (1966) Olesen, O.V.: The influence of disulfiram and calcium-carbimide on the serum diphenylhydantoin. Arch. Neurol. (Chic.) 16, 642-644 (1967) Rothstein, E.: Warfarin effect enhanced by disulfiram. J. Amer. med. Ass. 206, 15741575 (1968) Skovsted, L., Hansen, J.M., Kristensen, M., Christensen, L.K.: Inhibition of drug metabolism in man. Drug interactions. New York: Raven Press 1974 Spingler, H.: 0ber eine MSglichkeit zur colorimetrisehen Bestimmung von N-(4-Methyl-BenzolSulfonyl)-N-Butyl-Harnstoff in Serum. Klin. Wschr. 35, 533-535 (1957)
Dr. M. Kristensen Medicinsk afdeling C Diakonissestiftelsen Peter Bangsvej i DK-2OO0 Kobenhavn Denmark
The Influence of Disulfiram on the Half Life and Metabolic Clearance Rate of Diphenylhydantoin and Tolbutamide in Man T. Lysbo Svendsen, M. Brandt Kristensen, J. M¢lholm Hansen and L. Skovsted M e d i c a l Dept. C, D i a k o n i s s e s t i f t e l s e n , Copenhagen, Denmark
Received: accepted:
M a r c h 4, 1975, and in r e v i s e d S e p t e m b e r 3, 1975
and M e d i c a l
form:
Dept.
August
25,
F, G e n t o f t e H o s p i t a l ,
1975,
Summary.
D i p h e n y l h y d a n t o i n (DPH) and t o l b u t a m i d e serum levels were s t u d i e d in ten v o l u n t e e r s b e f o r e and a f t e r 4 days of d i s u l f i r a m treatment. The m e a n DPH half life i n c r e s e d s i g n i f i c a n t l y from 11.0 ± 1.2 h to 19.O ± 3.3 h, and the m e a n DPH m e t a b o l i c c l e a r a n c e rate d e c r e a s e d s i g n i f i c a n t l y from 51.2 ± 17.2 m l / m i n to 33.9 ± 12.O m l / m i n d u r i n g m e d i c a t i o n . No s i g n i f i c a n t c h a n g e s in the half life or m e t a b o l i c c l e a r a n c e rate of t o l b u t a m i d e was observed. Tolbutamide, s e r u m level.
Key words:
rate,
diphenylhydantoin,
In 1966 O l e s e n s h o w e d that a d m i n i s t r a tion of d i s u l f i r a m to p a t i e n t s on d i p h e n y l h y d a n t o i n (DPH) t r e a t m e n t res u l t e d in an i n c r e a s e d c o n c e n t r a t i o n of DPH in serum. The rise in s e r u m DPH was o b s e r v e d as early as four hours a f t e r i n g e s t i o n of d i s u l f i r a m . Later, he found a d e c r e a s e in the m e a n e x c r e t i o n of p a r a h y d r o x y - d i p h e n y l h y d a n t o i n (HPPH) (5-(p-hydroxyphenyl)-5-phenylhydantoin in urine d u r i n g a d m i n i s t r a t i o n of d i s u l f i r a m to D P H - t r e a t e d p a t i e n t s (Olesen, 1967). F r o m these f i n d i n g s he s u g g e s t e d that d i s u l f i r a m i n h i b i t e d the p a r a h y d r o x y l a t i o n of DPH, a p r o c e s s known to take place in the drug m e t a b o l i z i n g e n z y m e s y s t e m of the liver. The i n h i b i t i n g e f f e c t of d i s u l f i r a m on drug m e t a b o l i s m was later c o n f i r m e d by R o t h s t e i n (1968) and E l l i o t et al. (1971), w h o found an i n c r e a s e in the h a l f - l i f e of w a r f a r i n and antipyrin, respectively, after disulfiram treatment. The aim of the p r e s e n t i n v e s t i g a tion was to study w h e t h e r d i s u l f i r a m w o u l d also i n h i b i t the m e t a b o l i s m of t o l b u t a m i d e , w h i c h seemed of i n t e r e s t both from a t h e o r e t i c a l and a c l i n i c a l p o i n t of view.
drug
interaction,
disulfiram,
clearance
M A T E R I A L AND M E T H O D S Ten v o l u n t e e r s (2 females and 8 males, aged 22-72 yrs) were studied. The subjects did not r e c e i v e any drugs for at least one w e e k p r i o r to the study and none had any signs of renal or h e p a t i c disease. The h a l f - l i f e (T~) of t o l b u t a m i d e was d e t e r m i n e d by m e a s u r i n g its serum c o n c e n t r a t i o n 1.5, 3, 4.5, and 6 hours a f t e r i n t r a v e n o u s i n j e c t i o n of 500 mg t o l b u t a m i d e . The serum t o l b u t a m i d e conc e n t r a t i o n was d e t e r m i n e d by the m e t h o d d e s c r i b e d by S p i n g l e r (1957). The halflife was d e t e r m i n e d from these v a l u e s p l o t t e d a g a i n s t time on s e m i l o g a r i t h m i c paper. The h a l f - l i f e of DPH was d e t e r m i n e d after 100 mg of the drug l a b e l l e d w i t h 20 m i c r o c u r i e 14C I had been g i v e n intravenously. B l o o d samples were c o l l e c t e d 3, 6, 9 and 12 hours after the injection. DPH was e x t r a c t e d as d e s c r i b e d p r e v i o u s l y (Hansen et al., 1968). The r a d i o a c t i v i t y of the e x t r a c t s was p l o t -
l 5,5 diphenylhydantoin (4-14C) N.E.N.
440
ted against time on semilogarithmic p a p e r in o r d e r to d e t e r m i n e t h e h a l f life. T h e d i s t r i b u t i o n v o l u m e of t o l butamide and DPH was determined from the dose given and the concentration in serum at zero time found by extrapolat i o n of t h e h a l f - l i f e c u r v e . M e t a b o l i c c l e a r a n c e r a t e w a s c a l c u l a t e d as V D • In 2/T~. The half-life of both drugs was det e r m i n e d b e f o r e a n d a f t e r t r e a t m e n t for 4 days with disulfiram, which was given o r a l l y in the f o l l o w i n g d o s e s : Ist d a y 4 0 0 m g t h r e e t i m e s , 2 n d d a y 4 0 0 mg, a n d 3 r d a n d 4 t h d a y s 2 0 0 m g p e r day.
D P H of 73% a n d a d e c r e a s e in its m e a n m e t a b o l i c c l e a r a n c e r a t e of 34% w a s found after the disulfiram treatment. These changes were statistically s i g n i f i c a n t . T h e r e w a s no s i g n i f i c a n t a l t e r a t i o n in t h e d i s t r i b u t i o n volume of DPH. N o s i g n i f i c a n t c h a n g e s a f t e r d i s u l f i r a m t r e a t m e n t w e r e o b s e r v e d in a n y of t h e p a r a m e t e r s o f t o l b u t a m i d e metabolism studied.
DISCUSSION
RESULTS The results An increase
a r e g i v e n in T a b l e s I a n d in t h e m e a n h a l f - l i f e o f
2.
The finding that disulfiram increased the half-life and decreased the metab o l i c c l e a r a n c e r a t e of D P H w a s in a c c o r d a n c e w i t h t h e r e s u l t s of O l e s e n (1966, 1967), a n d s u g g e s t s t h a t disu!firam inhibits the hepatic metabo-
Table I. Pharmaeokinetic parameters of diphenylhydantoin before and during treatment with disulfiram Patient NO.
Half-life (hours)
Distribution (litre)
volume
Metabolic clearance rate (ml/min)
be fore
during
be fore
during
be fore
during
1
12.0
13.8
40.0
35.0
38.2
29.1
2
9.5
19.6
47.0
66.0
57.0
38.7
3
i0.0
21.8
32.0
39.O
36.2
20.6
4
12.3
18.O
84.O
81.O
78.4
52.1
5
ii .2
21.7
45.0
55.0
46.3
29.1
li.O ± 1.2
]9.0 -+ 3.3
49.6 -+ 20.0
55.2 + 19.O
51.2 _+ 17.2
33.9 ± 12.O
Mean value ± SD
0.01 < p < 0.02
N.S.
0.O01 < p < O.O1
Table 2. Pharmacokinetic parameters of tolbutamide before and during treatment with disulfiram Patient No.
Half-life (hours)
Distribution volume (litres)
Metabolic clearance rate (ml/min)
before
during
before
during
before
during
6
5 .O
5 .O
7
4.5
5.O
8
6.0
6.0
6.9
6.7
13.O
12.9
9
5.3
5.0
6.7
6.4
14.1
15.4
iO
5.5
5.8
6.7
6.7
14.0
13.4
5.2 ± 0.6
5.4 ± 0.5
6.8 a
6.6 a
13.7 a
13.9 a
Mean value ± SD a
Mean of 3 patients
441
l i s m of DPH. D P H is h y d r o x y l a t e d to H P P H w h i c h is e x c r e t e d by t h e k i d n e y s after glucuronidation. It is k n o w n t h a t t h i s p a r a h y d r o x y l a t i o n t a k e s p l a c e in t h e m i c r o s o m a l e n z y m e s y s t e m of t h e l i v e r in a n i m a l s as w e l l as in m a n . Tolbutamide is o x i d i z e d in t h e l i v e r to h y d r o x y m e t h y l t o l b u t a m i d e and carboxytolbutamide ( B ~ n d e r et al., 1956). T h i s p r o c e s s , too, t a k e s p l a c e in t h e microsomal e n z y m e s y s t e m in a n i m a l s a n d p r o b a b l y a l s o in m a n b u t d i r e c t e v i d e n c e of t h i s is l a c k i n g . A n u m b e r of d r u g s h a v e b e e n s h o w n to i n h i b i t t h e m e t a b o l i s m b o t h of D P H and tolbutamide in m a n , e.g. d i c o u m a r o l ( H a n s e n et al., 1966; K r i s t e n s e n et al., 1967), s u l f a p h e n a z o l e (Skovsted et al., 1974; C h r i s t e n s e n et al., 1963) , s u l f a methizole ( L u m h o l t z et al. 1975), oxyphenbutazone ( S k o v s t e d et al., 1974; Kristensen and Christensen, 1969), c h l o r amphenicol (Christensen and Skovsted, 1969), a n d c l o f i b r a t e ( S k o v s t e d et ai.1974). In v i e w of t h e s e s t u d i e s i t is s u r prising that disulfiram, as s h o w n here, d i d n o t i n f l u e n c e the m e t a b o l i s m of tolbutamide. A possible explanation c o u l d be t h a t d i s u l f i r a m is a m o r e s p e c i f i c i n h i b i t o r of t h e m i c r o s o m a l enzyme system than the other drugs mentioned above. If d i s u l f i r a m w e r e to i n h i b i t t h e metabolism of D P H c o m p e t i t i v e l y , a further possible explanation of t h e d i s crepancy might be that tolbutamide was g i v e n in a m u c h l a r g e r d o s e t h a n DPH. If t h i s w e r e c o r r e c t , it m i g h t b e e x pected that disulfiram would prolong t h e h a l f - l i f e of t o l b u t a m i d e g i v e n in a s m a l l e r dose. T h i s s u g g e s t i o n is b e i n g s t u d i e d at p r e s e n t . It is k n o w n t h a t d i s u l f i r a m g i v e n to p a t i e n t s t r e a t e d w i t h D P H c a n l e a d to DPH intoxication (Olesen, 1966). As it was impossible to s h o w an e f f e c t of disulfiram on tolbutamide metabolism t h e r e s e e m s no r i s k of a c c u m u l a t i o n of tolbutamide after administration of disulfiram.
REFERENCES B~nder, A., Scholz, J.: Tierexperimentelle Untersuchungen. Spezielle pharmakologische Untersuchungen mit D 860. Dtsch. med. Wschr. 81, 889-891 (1956)
Christensen, L.K., Hansen, J.M., Kristensen, M.: Sulphaphenazole induced hypoglycaemic attacks in tolbutamide-treated diabetics. Lancet 1963 II, 1298-1301 Christensen, L.K., Skovsted, L.: Inhibition of drug metabolism by chloramphenicol. Lancet 1969 II, 1397-1399 Elliot, S.V., Pasananti, G.T., Lee, C.H.: Impairment of drug metabolism by disulfiram in man. Clin. Pharmacol. Ther. 12, 785-792 (1971) Hansen, J.M., Kristensen, M., Skovsted, i., Christensen, L.K.: Dicoumarol-induced diphenylhydantoin intoxication. Lancet 1966 I L 265-266 Hansen, J.M., Kristensen, M., Skovsted, L.: Sulthiam (Ospolot ®) as inhibitor of diphenylhydantoin metabolism. Epilepsia 9, 17-22 (1968) Kristensen, M., Hansen, J.M.: Potentiation of the tolbutamide effect by dicoumarol. Diabetes 16, 211-214 (1967) Kristensen, M., Christensen, L.K.: Drug induced changes of the blood glucose lowering effect of oral hypoglycemic agents. Acta diabet. lat. VI (Suppl. i), 116-136 (1969) Lumholtz, B., Siersbaek Nielsen, K., Skovsted, L., Kampmann, J., Hansen, J.M.: Sulfamethizole induced inhibition of diphenylhydantoin, tolbutamide, and warfarin metabolism in man. Clin. Pharmacoi. Ther. 17, 731-734 (1975) Olesen, O.V.: Disulfiram (Antabuse ®) as inhibitor of phenytoin metabolism. Acta pharmacol. (Kbh.) 24, 317-322 (1966) Olesen, O.V.: The influence of disulfiram and calcium-carbimide on the serum diphenylhydantoin. Arch. Neurol. (Chic.) 16, 642-644 (1967) Rothstein, E.: Warfarin effect enhanced by disulfiram. J. Amer. med. Ass. 206, 15741575 (1968) Skovsted, L., Hansen, J.M., Kristensen, M., Christensen, L.K.: Inhibition of drug metabolism in man. Drug interactions. New York: Raven Press 1974 Spingler, H.: 0ber eine MSglichkeit zur colorimetrisehen Bestimmung von N-(4-Methyl-BenzolSulfonyl)-N-Butyl-Harnstoff in Serum. Klin. Wschr. 35, 533-535 (1957)
Dr. M. Kristensen Medicinsk afdeling C Diakonissestiftelsen Peter Bangsvej i DK-2OO0 Kobenhavn Denmark
