Br. J. clin. Pharmac. (1978), 6, 525-528
THE FEATURES OF HEPATIC ENZYME INDUCTION WITH GLUTETHIMIDE IN MAN L. JACKSON, M. HOMEIDA & C.J.C. ROBERTS Departments of Medicine and Pharmacology, University of Bristol, Bristol BS8 lTD
1 Sequential measurements of D-glucaric acid excretion were made in six healthy volunteers before, during and after 3 weeks' daily medication with glutethimide 500 mg. 2 There was a rapid rise in D-glucaric acid excretion within 2 days of starting medication and a rapid decline when it was stopped. 3 Antipyrine clearance and indocyanine green clearance were measured before and at the end of the 3 weeks' medication. 4 There was a 55% increase in antipyrine clearance but no change in indocyanine green clearance. 5 There was no correlation between antipyrine clearance and D-glucaric acid excretion. 6 Glutethimide causes rapid enzyme induction in man without concomitant rise in hepatic blood flow.
Introduiction
Glutethimide is a widely used hypnotic. It is highly lipid-soluble and its main route of elimination from the body is through hepatic metabolism (Curry, Riddall, Gordon, Simpson, Binns, Rondel & McMartin, 197 1). It has been shown to shorten warfarin plasma half life (Corn, 1966), to cause a fall in steady state plasma warfarin levels (MacDonald, Robinson, Sylwester & Jaffe, 1969) and to decrease the hypoprothrombinaemic effect of warfarin (Udall, 1975) by hepatic microsomal enzyme induction. Detailed studies in man on the potency of glutethimide as an enzyme inducing agent have not hitherto been performed. The aim of this study was to characterise the enzyme inducing effect of glutethimide in terms of potency and time course and to assess its usefulness for future clinical experimentation. The design of the study allowed an examination of the interrelationship between two measurements of enzyme induction-antipyrine clearance (Stevenson, 1977) and i-glucaric acid excretion (Hunter, Maxwell, Carella, Stewart & Williams, 1973)-and further investigation of the effect of enzyme induction on hepatic blood flow in man (Roberts, Jackson, Halliwell & Branch, 1976).
medication. They consumed a normal diet but alcohol intake was limited during the 33 days of the study period. Each subject took glutethimide 500mg at bedtime on days 8 to 28. The timing of collections and investigations was decided from the results of a pilot study. Twenty-four hour urine collections were made on days 1 to 5, 8 to 12, 14, 21 and 28 to 33. After measurement of volume aliquots of urine were stored at -10°C and subsequently urinary D-glucaric acid was assayed by the method of Marsh (1963), as modified by Simmons, Davis, Dordoni & Williams (1974). Indocyanine green kinetics were measured on the fasting subjects after 40min rest in the sitting position on days 8 and 29, using the sampling procedure previously described (Roberts et al., 1976). Plasma indocyanine green was assayed by the method of Caesar, Shaldon, Chiandussi, Guevara & Sherlock (1961). Antipyrine kinetics were also measured on days 8 and 29 using the procedure previously described (Roberts et al., 1976). Plasma antipyrine was measured by the method of Brodie, Axelrod, Soberman & Levy (1949). Plasma half-life, volume of distribution and blood clearances of indocyanine green and antipyrine were calculated from the log plasma concentration time plots (Roberts et aL, 1976).
Method Results
Six healthy volunteers aged 20 to 23 years took part in the study which was approved by the ethics committee of Bristol Royal Infirmary. The subjects were nonsmokers and were not taking any concurrent
The D-glucaric acid excretion before, during and after glutethimide 500 mg daily for 3 weeks is shown in Figure 1. There was a substantial rise in D-glucaric
526
L. JACKSON, M. HOMEIDA & C.J.C. ROBERTS
the clearance, plasma half-life or volume of distribution of indocyanine green. There was no correlation between the clearance of antipyrine and D-glucaric acid excretion either before or after glutethimide and no correlation between the percentage change in the two parameters. Glutethimide was well tolerated but a seventh subject was withdrawn because of the appearance of skin rash.
-
E -6
0 a) x
a)
0 co 0
Discussion
co 0
-5)
14 18 22 26 30 34 Time (days) Figure 1 D-glucaric acid excretion (mean ± s.e. mean) before, during and following 3 weeks' daily administration of glutethimide 500mg (days 8-28 inclusive) to six healthy individuals.
o 2
6
10
acid excretion in the first two days of medication. The highest excretion was that obtained after 3 weeks' medication. D-glucaric acid excretion returned to normal values during 5 days after stopping glutethimide. The results of antipyrine and indocyanine green kinetics before and after glutethimide are shown in Tables 1 and 2. There was a significant 55% increase in antipyrine clearance accompanied by a 31% fall in antipyrine plasma half-life. There was no change in the volume of distribution of antipyrine and no change in
This study has shown glutethimide to be a potent enzyme inducing agent in man. Sequential D-glucaric acid excretion measurements have demonstrated that the onset and decay of the effect are rapid. Enzyme induction with glutethimide is not accompanied by an increase in liver blood flow in man. Glutethimide has been shown to cause hepatic microsomal enzyme induction in rats (Conney, 1967), and to interact with warfarin in man (Corn, 1966; MacDonald et al., 1969; Udall, 1975). Patients tolerant to glutethimide metabolise the drug more rapidly than normal persons (Schmid, Cornu, Imhof & Kebrele, 1964) and long term treatment has been associated with osteomalacia (Greenwood, Prunty & Silver, 1973). The 55% increase in antipyrine clearance in this study provides evidence that glutethimide 500 mg can cause substantial enzyme induction in man. This increase was, however, smaller than that previously observed with phenobarbitone 180 mg (90%) (Roberts et al., 1976). The greater part of the rise in D-glucaric acid excretion occurred within two days of starting
Table 1 Parameters of antipyrine disposition in six healthy volunteers before and after 3 weeks' daily medication with glutethimide 500 mg Antipyrine disposition
Subject
Before glutethimide Volume of Plasma Cmlearance distribution haff-life (mi/rn/n
Cmlearance 2 3 4 5 6 Mean
95% confidence
44 53 43 41 34 48 44 31-57
(h)
41 54 44 39 56 47 47
33-60
11 12 12 11 19 11
13 7-19
limits *
P
THE FEATURES OF HEPATIC ENZYME INDUCTION WITH GLUTETHIMIDE IN MAN L. JACKSON, M. HOMEIDA & C.J.C. ROBERTS Departments of Medicine and Pharmacology, University of Bristol, Bristol BS8 lTD
1 Sequential measurements of D-glucaric acid excretion were made in six healthy volunteers before, during and after 3 weeks' daily medication with glutethimide 500 mg. 2 There was a rapid rise in D-glucaric acid excretion within 2 days of starting medication and a rapid decline when it was stopped. 3 Antipyrine clearance and indocyanine green clearance were measured before and at the end of the 3 weeks' medication. 4 There was a 55% increase in antipyrine clearance but no change in indocyanine green clearance. 5 There was no correlation between antipyrine clearance and D-glucaric acid excretion. 6 Glutethimide causes rapid enzyme induction in man without concomitant rise in hepatic blood flow.
Introduiction
Glutethimide is a widely used hypnotic. It is highly lipid-soluble and its main route of elimination from the body is through hepatic metabolism (Curry, Riddall, Gordon, Simpson, Binns, Rondel & McMartin, 197 1). It has been shown to shorten warfarin plasma half life (Corn, 1966), to cause a fall in steady state plasma warfarin levels (MacDonald, Robinson, Sylwester & Jaffe, 1969) and to decrease the hypoprothrombinaemic effect of warfarin (Udall, 1975) by hepatic microsomal enzyme induction. Detailed studies in man on the potency of glutethimide as an enzyme inducing agent have not hitherto been performed. The aim of this study was to characterise the enzyme inducing effect of glutethimide in terms of potency and time course and to assess its usefulness for future clinical experimentation. The design of the study allowed an examination of the interrelationship between two measurements of enzyme induction-antipyrine clearance (Stevenson, 1977) and i-glucaric acid excretion (Hunter, Maxwell, Carella, Stewart & Williams, 1973)-and further investigation of the effect of enzyme induction on hepatic blood flow in man (Roberts, Jackson, Halliwell & Branch, 1976).
medication. They consumed a normal diet but alcohol intake was limited during the 33 days of the study period. Each subject took glutethimide 500mg at bedtime on days 8 to 28. The timing of collections and investigations was decided from the results of a pilot study. Twenty-four hour urine collections were made on days 1 to 5, 8 to 12, 14, 21 and 28 to 33. After measurement of volume aliquots of urine were stored at -10°C and subsequently urinary D-glucaric acid was assayed by the method of Marsh (1963), as modified by Simmons, Davis, Dordoni & Williams (1974). Indocyanine green kinetics were measured on the fasting subjects after 40min rest in the sitting position on days 8 and 29, using the sampling procedure previously described (Roberts et al., 1976). Plasma indocyanine green was assayed by the method of Caesar, Shaldon, Chiandussi, Guevara & Sherlock (1961). Antipyrine kinetics were also measured on days 8 and 29 using the procedure previously described (Roberts et al., 1976). Plasma antipyrine was measured by the method of Brodie, Axelrod, Soberman & Levy (1949). Plasma half-life, volume of distribution and blood clearances of indocyanine green and antipyrine were calculated from the log plasma concentration time plots (Roberts et aL, 1976).
Method Results
Six healthy volunteers aged 20 to 23 years took part in the study which was approved by the ethics committee of Bristol Royal Infirmary. The subjects were nonsmokers and were not taking any concurrent
The D-glucaric acid excretion before, during and after glutethimide 500 mg daily for 3 weeks is shown in Figure 1. There was a substantial rise in D-glucaric
526
L. JACKSON, M. HOMEIDA & C.J.C. ROBERTS
the clearance, plasma half-life or volume of distribution of indocyanine green. There was no correlation between the clearance of antipyrine and D-glucaric acid excretion either before or after glutethimide and no correlation between the percentage change in the two parameters. Glutethimide was well tolerated but a seventh subject was withdrawn because of the appearance of skin rash.
-
E -6
0 a) x
a)
0 co 0
Discussion
co 0
-5)
14 18 22 26 30 34 Time (days) Figure 1 D-glucaric acid excretion (mean ± s.e. mean) before, during and following 3 weeks' daily administration of glutethimide 500mg (days 8-28 inclusive) to six healthy individuals.
o 2
6
10
acid excretion in the first two days of medication. The highest excretion was that obtained after 3 weeks' medication. D-glucaric acid excretion returned to normal values during 5 days after stopping glutethimide. The results of antipyrine and indocyanine green kinetics before and after glutethimide are shown in Tables 1 and 2. There was a significant 55% increase in antipyrine clearance accompanied by a 31% fall in antipyrine plasma half-life. There was no change in the volume of distribution of antipyrine and no change in
This study has shown glutethimide to be a potent enzyme inducing agent in man. Sequential D-glucaric acid excretion measurements have demonstrated that the onset and decay of the effect are rapid. Enzyme induction with glutethimide is not accompanied by an increase in liver blood flow in man. Glutethimide has been shown to cause hepatic microsomal enzyme induction in rats (Conney, 1967), and to interact with warfarin in man (Corn, 1966; MacDonald et al., 1969; Udall, 1975). Patients tolerant to glutethimide metabolise the drug more rapidly than normal persons (Schmid, Cornu, Imhof & Kebrele, 1964) and long term treatment has been associated with osteomalacia (Greenwood, Prunty & Silver, 1973). The 55% increase in antipyrine clearance in this study provides evidence that glutethimide 500 mg can cause substantial enzyme induction in man. This increase was, however, smaller than that previously observed with phenobarbitone 180 mg (90%) (Roberts et al., 1976). The greater part of the rise in D-glucaric acid excretion occurred within two days of starting
Table 1 Parameters of antipyrine disposition in six healthy volunteers before and after 3 weeks' daily medication with glutethimide 500 mg Antipyrine disposition
Subject
Before glutethimide Volume of Plasma Cmlearance distribution haff-life (mi/rn/n
Cmlearance 2 3 4 5 6 Mean
95% confidence
44 53 43 41 34 48 44 31-57
(h)
41 54 44 39 56 47 47
33-60
11 12 12 11 19 11
13 7-19
limits *
P
