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The effect of cimetidine and ranitidine on serum high density lipoprotein subfractions
Atherosclerosis, 51(1985) Elsevier
159
159-162
ATH 03663
The Effect of Cimetidine and Ranitidine on Serum High Density Lipoprotein Subfractions
Teik C. Ooi I, Norman R. Peden I, Malcolm and Eva I. Simo 1 Divisions of
C. Champion
2
’Endocrinology and Metabolism and 2 Gastroenterology, Department of Medicine, Ottawu Civic Hospital, University of Ottawa, Ottawa, Ontario (Canada) (Received 29 October, 1984) (Revised, received 1 March, 1985) (Accepted 5 March, 1985)
Summary
Of the two major subfractions of high density lipoprotein (HDL), HDL, cholesterol (HDL,-C) and not HDL, cholesterol (HDL,-C) correlates negatively with coronary heart disease. To study the effect of cimetidine and ranitidine on HDL subfractions, 6 healthy males received cimetidine (600 mg bid) ranitidine (150 mg bid) and placebo (one tab bid) for 1 week each, in random order. Measurements of HDL cholesterol (HDL-C), HDL,-C, HDL,-C were made on day 7 of each week. Comparing cimetidine with placebo, HDL,-C/HDL-C, HDL,-C/total cholesterol and HDL,-C/HDL,-C increased significantly while HDL,-C/HDL-C decreased. There was no difference in HDL-C parameters between ranitidine and placebo. Cimetidine treatment results in redistribution of HDL subfractions in favour of HDL,. The mechanism is not Hz-receptor antagonism as ranitidine had no such effect. Key words: Cimetidine - High density lipoprotein subfractions - Ranitidine
Correspondence Hospital, Ottawa,
0021-9150/85/$03.30
and reprints: Dr. T.C. Ooi, Division Ontario, Canada KlY 4E9.
0 1985 Elsevier Scientific
of Endocrinology
Publishers
Ireland,
Ltd.
and Metabolism,
Ottawa
Civic
160
Introduction
An inverse relationship exists between the levels of plasma high density lipoprotein (HDL) cholesterol and coronary heart disease [l]. Of the 2 major subfractions of HDL, HDL, cholesterol (HDL,-C) and not HDL, cholesterol (HDL,-C) correlates negatively with coronary heart disease [2]. HDL cholesterol (HDL-C) level is affected by many drugs [3] but very little is known about the effect of cimetidine, a widely used Hz-receptor antagonist. In one study cimetidine given for 1 month to healthy subjects increased HDL-C, although, the authors were unable to demonstrate any significant change in HDL,-C and HDL,-C levels [4]. Treatment with cimetidine was also associated with an increase in HDL-C in a single patient with familial type III hyperlipoproteinemia [5]. In a placebo-controlled study, we have examined the effect of short-term administration of cimetidine and ranitidine (another HI-receptor antagonist) on HDL subfractions in normal subjects. Methods
In a randomised cross-over trial, 6 healthy drug-free males (aged 24-36 years) were treated for 3 consecutive periods of 7 days with cimetidine (Tagamet, Smith Kline and French, Canada) one tablet (600 mg) twice daily, ranitidine (Zantac, Glaxo, Canada) one tablet (150 mg) twice daily and a placebo, one tablet twice daily. On the 7th day of each treatment period, after an overnight fast, subjects took their morning medication with water at 07.30 h and attended the Metabolic Laboratory to have a blood sample taken at 08.30 h, after 30 min of rest. Serum was separated and stored at - 20°C. All samples from all 6 subjects were assayed in the same batch. The following measurements were made: total cholesterol (TC), total triglycerides (TTg), total HDL-C, HDL,-C, HDL,-C, testosterone and dehydroepiandrosterone-sulphate (DHEA-S). Serum cholesterol was measured by an enzymatic CHOD-PAP method (Boehringer Mannheim Canada Ltd.). HDL-C was measured after a single precipitation procedure with heparin and manganese [6] and HDL-C subfractions were measured after double precipitation with heparin/manganese and then dextran sulphate (molecular weight 15000, obtained from Sochibo, 3-5 rue Carnot, 92100 Boulogne sur Seine, France) [7]. Serum triglycerides were measured enzymatically using the a-gent Triglycerides Test System on the Abbott-200 analyser. Low density lipoprotein cholesterol (LDL-C) was calculated according to the method of Friedewald et al. [8]. The coefficients of variation of the HDL-C assays are as follows:
Total HDL-C HDL,-C HDL,-C
Within assay (n = 11)
Between assay (n = 10)
0.9% 2.9% 1 .O%
4.5% 9.0% 4.5%
161
P
Fig. 1. Parameters (P) and cimetidine
c
P
c
of high density lipoprotein (C) treatment. Horizontal
cholesterol (HDL-C) subfractions after 1 week of placebo line (-) represents mean value. NS = not significant.
Serum testosterone and DHEA-S were measured by direct using the RSL Nosolvex kit and the Pantex kit respectively. Statistical analysis was by the 2-tail paired r-test.
radioimmunoassay
Results Results of HDL-C subfractions are shown in Fig. 1. Comparing cimetidine with placebo, the percentages of HDL,-C/HDL-C and HDL,-C/TC were significantly higher following cimetidine treatment. Conversely, the percentage of HDL,-C/HDL-C was significantly lower with cimetidine treatment. The ratio of HDL~-C/HDLj-C was also greater following cimetidine treatment and this was primarily due to a higher HDL,-C in 5 of the 6 subjects. However, the difference in HDL,-C did not quite attain statistical significance (P = 0.092). There was no difference in HDL-C. There was no difference in any of the HDL-C parameters between treatment with ranitidine and cimetidine or placebo. Following placebo and ranitidine, the results (in mmol/l, mean f SD) were: HDL-C, 1.19 * 0.17 and 1.22 f 0.20; HDL,-C, 0.28 f. 0.11 and 0.28 + 0.15; HDL,-C, 0.93 k 0.13 and 0.94 + 0.18, respectively. No difference was noted in TC, TTg, and LDL-C among any of the 3 treatment groups. Following placebo, cimetidine and ranitidine, the results (in mmol/l, mean + SD) were: TC, 4.62 * 0.79, 4.67 + 0.80 and 4.67 f 0.95; TTg, 1.18 + 0.53, 1.18 _t 0.50 and 0.98 * 0.37; LDL-C, 2.89 + 0.65, 2.85 + 0.54 and 3.01 + 0.79, respectively. There was no difference in serum testosterone and DHEA-S among any of the 3 groups. The results following placebo, cimetidine and ranitidine for testosterone (in nmol/l, mean k SD) were 25.58 t- 5.64, 25.33 + 6.65 and 23.0 + 4.05 and for serum
I62
DHEA-S (in pmol/l, tively.
mean k SD) 8.43 & 1.20, 10.42 f 3.63 and 8.36 & 1.57, respec-
Discussion
This study shows that cimetidine, given for as short a period as 1 week, has effects on HDL metabolism in normal subjects. The effect seems to be a redistribution of the 2 major subfractions of HDL, resulting in an increased proportion of HDL,-C and a decreased proportion of HDL,-C. Since HDL,-C is associated with reduced risk of coronary heart disease [2], this effect of cimetidine may prove to be of clinical significance. The concomitant increase in HDL,-C/HDL-C percentage and decrease in HDL,-C/HDL-C percentage could account for the lack of change seen in HDL-C, although longer term administration of cimetidine has been reported to result in an increase in HDL-C [4,5]. Extrapolating from our results, any increase in HDL-C would most likely be due to an increase in HDL,-C. This study does not delineate the mechanism involved in the effect of cimetidine on HDL metabolism. It does, however, suggest that it is unlikely to be related to HZ-receptor antagonism since ranitidine did not have a similar effect. Other postulated mechanisms [5] include inhibition of hepatic microsomal enzyme activity [8] and the antiandrogenic effects [9] which occur with cimetidine and not ranitidine. We have not demonstrated any change in serum testosterone or DHEA-S levels following cimetidine therapy. However, the antiandrogenic effect of cimetidine may be at receptor level. We are currently examining the effect of cimetidine on apoproteins which may help clarify the mechanism involved. References concentration and development of 1 Miller, G.J. and Miller, N.E., Plasma high-density-lipoprotein ischaemic heart disease, Lancet, i (1975) 16. F.C., Clark, R.S., Simpson, H.S. and Ballantyne, D., High density and low density 2 Ballantyne, lipoprotein subfractions in survivors of myocardial infarction and in control subjects, Metabolism, 31 (1982) 433. P.N., High-density lipoprotein cholesterol - Methods and clinical significance, Crit. Rev. 3 Durrington, Clin. Lab. Sci., 18 (1982) 31. T.K., Ene, M.D. et al., The effects of cimetidine on serum and lipoprotein 4 Bolton, C.H., Daneshmend, lipids in normal subjects, Brit. J. Clin. Pharmacol., 15 (1983) 152. 5 Miller, N.E. and Lewis, B., Cimetidine and HDL cholesterol, Lancet, i (1983) 529. evaluation of the heparin-manganese precipitation 6 Warnick, G.R. and Albers, J.J., A comprehensive procedure for estimating high density lipoprotein cholesterol, J. Lipid Res., 19 (1978) 65. and quantitation of 7 Gidez, L.I., Miller, G.J., Burstein, M., Slagle, S. and Eder, H.A., Separation subclasses of human plasma high density lipoproteins by a simple precipitation procedure, J. Lipid Res., 23 (1982) 1206. D.S., Estimation of the concentration of low-density 8 Friedewald, W.T., Levy, RI. and Frederickson, lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge, Clin. Chem., 18 (1972) 499. 9 Henry, D.A., MacDonald, I.A., Kitchingman, G., Bell, G.D. and Langman, M.J.S., Cimetidine and ranitidine - Comparison of effects on hepatic drug metabolism, Brit. Med. J., 281 (1980) 775. 10 Peden, N.R., Boyd, E.J.S., Browning, M.C.K., Saunders, J.H.B. and Wormsley, K.G., Effect of treatment with two histamine Hz-receptor antagonists on basal levels of luteinising hormone, thyroid stimulating hormone, prolactin, testosterone and oestradiol-17-B in men with duodenal ulcer, Acta Endocrinol., 96 (1981) 564.
159
159-162
ATH 03663
The Effect of Cimetidine and Ranitidine on Serum High Density Lipoprotein Subfractions
Teik C. Ooi I, Norman R. Peden I, Malcolm and Eva I. Simo 1 Divisions of
C. Champion
2
’Endocrinology and Metabolism and 2 Gastroenterology, Department of Medicine, Ottawu Civic Hospital, University of Ottawa, Ottawa, Ontario (Canada) (Received 29 October, 1984) (Revised, received 1 March, 1985) (Accepted 5 March, 1985)
Summary
Of the two major subfractions of high density lipoprotein (HDL), HDL, cholesterol (HDL,-C) and not HDL, cholesterol (HDL,-C) correlates negatively with coronary heart disease. To study the effect of cimetidine and ranitidine on HDL subfractions, 6 healthy males received cimetidine (600 mg bid) ranitidine (150 mg bid) and placebo (one tab bid) for 1 week each, in random order. Measurements of HDL cholesterol (HDL-C), HDL,-C, HDL,-C were made on day 7 of each week. Comparing cimetidine with placebo, HDL,-C/HDL-C, HDL,-C/total cholesterol and HDL,-C/HDL,-C increased significantly while HDL,-C/HDL-C decreased. There was no difference in HDL-C parameters between ranitidine and placebo. Cimetidine treatment results in redistribution of HDL subfractions in favour of HDL,. The mechanism is not Hz-receptor antagonism as ranitidine had no such effect. Key words: Cimetidine - High density lipoprotein subfractions - Ranitidine
Correspondence Hospital, Ottawa,
0021-9150/85/$03.30
and reprints: Dr. T.C. Ooi, Division Ontario, Canada KlY 4E9.
0 1985 Elsevier Scientific
of Endocrinology
Publishers
Ireland,
Ltd.
and Metabolism,
Ottawa
Civic
160
Introduction
An inverse relationship exists between the levels of plasma high density lipoprotein (HDL) cholesterol and coronary heart disease [l]. Of the 2 major subfractions of HDL, HDL, cholesterol (HDL,-C) and not HDL, cholesterol (HDL,-C) correlates negatively with coronary heart disease [2]. HDL cholesterol (HDL-C) level is affected by many drugs [3] but very little is known about the effect of cimetidine, a widely used Hz-receptor antagonist. In one study cimetidine given for 1 month to healthy subjects increased HDL-C, although, the authors were unable to demonstrate any significant change in HDL,-C and HDL,-C levels [4]. Treatment with cimetidine was also associated with an increase in HDL-C in a single patient with familial type III hyperlipoproteinemia [5]. In a placebo-controlled study, we have examined the effect of short-term administration of cimetidine and ranitidine (another HI-receptor antagonist) on HDL subfractions in normal subjects. Methods
In a randomised cross-over trial, 6 healthy drug-free males (aged 24-36 years) were treated for 3 consecutive periods of 7 days with cimetidine (Tagamet, Smith Kline and French, Canada) one tablet (600 mg) twice daily, ranitidine (Zantac, Glaxo, Canada) one tablet (150 mg) twice daily and a placebo, one tablet twice daily. On the 7th day of each treatment period, after an overnight fast, subjects took their morning medication with water at 07.30 h and attended the Metabolic Laboratory to have a blood sample taken at 08.30 h, after 30 min of rest. Serum was separated and stored at - 20°C. All samples from all 6 subjects were assayed in the same batch. The following measurements were made: total cholesterol (TC), total triglycerides (TTg), total HDL-C, HDL,-C, HDL,-C, testosterone and dehydroepiandrosterone-sulphate (DHEA-S). Serum cholesterol was measured by an enzymatic CHOD-PAP method (Boehringer Mannheim Canada Ltd.). HDL-C was measured after a single precipitation procedure with heparin and manganese [6] and HDL-C subfractions were measured after double precipitation with heparin/manganese and then dextran sulphate (molecular weight 15000, obtained from Sochibo, 3-5 rue Carnot, 92100 Boulogne sur Seine, France) [7]. Serum triglycerides were measured enzymatically using the a-gent Triglycerides Test System on the Abbott-200 analyser. Low density lipoprotein cholesterol (LDL-C) was calculated according to the method of Friedewald et al. [8]. The coefficients of variation of the HDL-C assays are as follows:
Total HDL-C HDL,-C HDL,-C
Within assay (n = 11)
Between assay (n = 10)
0.9% 2.9% 1 .O%
4.5% 9.0% 4.5%
161
P
Fig. 1. Parameters (P) and cimetidine
c
P
c
of high density lipoprotein (C) treatment. Horizontal
cholesterol (HDL-C) subfractions after 1 week of placebo line (-) represents mean value. NS = not significant.
Serum testosterone and DHEA-S were measured by direct using the RSL Nosolvex kit and the Pantex kit respectively. Statistical analysis was by the 2-tail paired r-test.
radioimmunoassay
Results Results of HDL-C subfractions are shown in Fig. 1. Comparing cimetidine with placebo, the percentages of HDL,-C/HDL-C and HDL,-C/TC were significantly higher following cimetidine treatment. Conversely, the percentage of HDL,-C/HDL-C was significantly lower with cimetidine treatment. The ratio of HDL~-C/HDLj-C was also greater following cimetidine treatment and this was primarily due to a higher HDL,-C in 5 of the 6 subjects. However, the difference in HDL,-C did not quite attain statistical significance (P = 0.092). There was no difference in HDL-C. There was no difference in any of the HDL-C parameters between treatment with ranitidine and cimetidine or placebo. Following placebo and ranitidine, the results (in mmol/l, mean f SD) were: HDL-C, 1.19 * 0.17 and 1.22 f 0.20; HDL,-C, 0.28 f. 0.11 and 0.28 + 0.15; HDL,-C, 0.93 k 0.13 and 0.94 + 0.18, respectively. No difference was noted in TC, TTg, and LDL-C among any of the 3 treatment groups. Following placebo, cimetidine and ranitidine, the results (in mmol/l, mean + SD) were: TC, 4.62 * 0.79, 4.67 + 0.80 and 4.67 f 0.95; TTg, 1.18 + 0.53, 1.18 _t 0.50 and 0.98 * 0.37; LDL-C, 2.89 + 0.65, 2.85 + 0.54 and 3.01 + 0.79, respectively. There was no difference in serum testosterone and DHEA-S among any of the 3 groups. The results following placebo, cimetidine and ranitidine for testosterone (in nmol/l, mean k SD) were 25.58 t- 5.64, 25.33 + 6.65 and 23.0 + 4.05 and for serum
I62
DHEA-S (in pmol/l, tively.
mean k SD) 8.43 & 1.20, 10.42 f 3.63 and 8.36 & 1.57, respec-
Discussion
This study shows that cimetidine, given for as short a period as 1 week, has effects on HDL metabolism in normal subjects. The effect seems to be a redistribution of the 2 major subfractions of HDL, resulting in an increased proportion of HDL,-C and a decreased proportion of HDL,-C. Since HDL,-C is associated with reduced risk of coronary heart disease [2], this effect of cimetidine may prove to be of clinical significance. The concomitant increase in HDL,-C/HDL-C percentage and decrease in HDL,-C/HDL-C percentage could account for the lack of change seen in HDL-C, although longer term administration of cimetidine has been reported to result in an increase in HDL-C [4,5]. Extrapolating from our results, any increase in HDL-C would most likely be due to an increase in HDL,-C. This study does not delineate the mechanism involved in the effect of cimetidine on HDL metabolism. It does, however, suggest that it is unlikely to be related to HZ-receptor antagonism since ranitidine did not have a similar effect. Other postulated mechanisms [5] include inhibition of hepatic microsomal enzyme activity [8] and the antiandrogenic effects [9] which occur with cimetidine and not ranitidine. We have not demonstrated any change in serum testosterone or DHEA-S levels following cimetidine therapy. However, the antiandrogenic effect of cimetidine may be at receptor level. We are currently examining the effect of cimetidine on apoproteins which may help clarify the mechanism involved. References concentration and development of 1 Miller, G.J. and Miller, N.E., Plasma high-density-lipoprotein ischaemic heart disease, Lancet, i (1975) 16. F.C., Clark, R.S., Simpson, H.S. and Ballantyne, D., High density and low density 2 Ballantyne, lipoprotein subfractions in survivors of myocardial infarction and in control subjects, Metabolism, 31 (1982) 433. P.N., High-density lipoprotein cholesterol - Methods and clinical significance, Crit. Rev. 3 Durrington, Clin. Lab. Sci., 18 (1982) 31. T.K., Ene, M.D. et al., The effects of cimetidine on serum and lipoprotein 4 Bolton, C.H., Daneshmend, lipids in normal subjects, Brit. J. Clin. Pharmacol., 15 (1983) 152. 5 Miller, N.E. and Lewis, B., Cimetidine and HDL cholesterol, Lancet, i (1983) 529. evaluation of the heparin-manganese precipitation 6 Warnick, G.R. and Albers, J.J., A comprehensive procedure for estimating high density lipoprotein cholesterol, J. Lipid Res., 19 (1978) 65. and quantitation of 7 Gidez, L.I., Miller, G.J., Burstein, M., Slagle, S. and Eder, H.A., Separation subclasses of human plasma high density lipoproteins by a simple precipitation procedure, J. Lipid Res., 23 (1982) 1206. D.S., Estimation of the concentration of low-density 8 Friedewald, W.T., Levy, RI. and Frederickson, lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge, Clin. Chem., 18 (1972) 499. 9 Henry, D.A., MacDonald, I.A., Kitchingman, G., Bell, G.D. and Langman, M.J.S., Cimetidine and ranitidine - Comparison of effects on hepatic drug metabolism, Brit. Med. J., 281 (1980) 775. 10 Peden, N.R., Boyd, E.J.S., Browning, M.C.K., Saunders, J.H.B. and Wormsley, K.G., Effect of treatment with two histamine Hz-receptor antagonists on basal levels of luteinising hormone, thyroid stimulating hormone, prolactin, testosterone and oestradiol-17-B in men with duodenal ulcer, Acta Endocrinol., 96 (1981) 564.