Lipid Metabolism—HDL

Houck, Jacob and Maengwyn-Davies, Journal of Clinical Investigation (1960),172 showed a decrease in dermal lipids in rats treated with PHT (25 mg/day, for two to six-teen days).

172. Houck, J. C., Jacob, R. A., and Maengwyn-Davies, G. D., The effect of sodium Dilantin administration upon the chemistry of the skin, J. Clin. Invest., 39: 1758-1762, 1960.

Nakamura and Masuda, Archives Internationales de Pharmacodynamie et de Therapie (1966),265 demonstrated a marked decrease in dermal lipids (triglycerides, cholesterol and phospholipids) and a decrease in the conversion of [14C]-acetate into these compounds with PHT (50 mg/kg/ day) for five weeks.

265. Nakamura, K. and Masuda, Y., Effects of 5,5-diphenylhydantoin3-ethoxycarbonyl-5,5-diphenylhydantoin (P-6127) on the dermal and gingival tissues of experimental animals, Arch. Int. Pharmacodyn., 162: 255-264, 1966.

Chung, Journal of Atherosclerosis Research (1967),56 studied the effect of PHT on aortic lipid concentrations. Daily oral administration of PHT (50 mg/day) to rabbits for thirty days resulted in significant reduction of aortic concentrations of cholesterol and phospholipids, and an increase in triglyceride concentration. No significant changes in concentrations of these lipids were noted in liver or plasma. These effects of PHT were not observed when an atherogenic diet was fed to the rabbits.

56. Chung, A. C., The influence of diphenyihydantoin (Dilantin) on the development of atherosclerosis in rabbits, J. Atheroscler. Res., 7: 373-379, 1967.

Ariyoshi and Remmer, Naunyn-Schmiedeberg Archiv fur Pharmakologie (1968),529 found that, in rats, PHT (80 mg/kg, for six days) had a protective effect on the fatty infiltration of the liver produced by alcohol or a choline-free diet.

529. Ariyoshi, V. T. and Remmer, H., The action of phenobarbital and diphenylhydantoin on various fat fractions of liver, Naunyn-Schmiedeberg Arch. Pharm., 260: 90-91, 1968.

Nikkila, Kaste, Ehnholm and Viikari, Acta Medica Scandinavica (1978),2002 measured the serum high-density lipoproteins (HDL) and other lipoprotein and apolipo-protein A levels in twenty-eight epileptic patients who received PHT as their only medication and in forty-four healthy male and forty-nine female controls. The patients treated with PHT had significantly higher HDL levels than the controls. The authors state that since serum HDL shows an inverse correlation with the risk of coronary heart disease, epileptic patients taking PHT may be protected from this disease.

2002. Nikkila, E. A., Kaste, M., Ehnholm, C. and Viikari, J., Elevation of high-density lipoprotein in epileptic patients treated with phenytoin, Acta Med. Scand, 204: 517-20, 1978.

Luoma, Sotaniemi, Pelkonen and Myllyla, Scandinavian Journal of Clinical and Laboratory Investigation (1980),2740 studied plasma HDL-cholesterol (HDL-C) and hepatic cytochrome P-450 concentrations in eighteen epileptic patients (twelve on PHT alone, five on PHT plus other antiepileptics, and one on carbamazepine alone) who were undergoing diagnostic liver biopsy because of altered hepatic function. Mean HDL-C levels and cytochrome P-450 concentrations were higher in the PHT-alone group than in controls, but not as high as those in the polytherapy group. Serum triglyceride level was inversely related to the hepatic cytochrome P-450 content. The authors conclude that increased plasma HDL-C levels in the treated patients correlate with drug-induced hepatic microsomal enzyme activity.

2740. Luoma, P. V., Sotaniemi, E. A., Pelkonen, R. O., Myllyla, V. V., Plasma high-density lipoprotein cholesterol and hepatic cytochrome P-450 concentrations in epileptics undergoing anticonvulsant treatment, Scand. J. Clin. Lab. Invest., 40: 163-67, 1980.

Luoma, Myllyla, Sotaniemi, Lehtinen and Hokkanen, European Neurology (1980),2734 compared HDL-C levels in forty-three normal subjects to those in ninety-seven patients on long-term therapy with PHT, carbamazepine and phenobarbital, alone or in combination. Thirty-eight patients on PHT alone and eleven on PHT plus phenobarbital had significantly higher HDL-C levels than controls. HDL-C to total cholesterol ratios were also increased. Patients on carbamazepine alone (twenty) did not show increased HDL-C levels.

2734. Luoma, P. V., Myllyla, V. V., Sotaniemi, E. A., Lehtinen, I. A., Hokkanen, E. J., Plasma high-density lipoprotein cholesterol in epileptics treated with various anticonvulsants, Eur. Neurol., 19; 67-72,1980.

Nencini, Pharmacological Research Communications (1982),2821 reported that PHT (10-100 µM) increased cyclic AMP levels and free fatty acid release under resting conditions, and with isoprenaline treatment, in rat brown adipose tissue. Ouabain, as well as lowered intracellular sodium and potassium, inhibited these effects.

2821. Nencini, P., Phenytoin induces cyclic-AMP accumulation and free fatty acids release in rat brown adipose tissue, Pharmacol. Res. Commun., 14(7): 593-604, 1982.

Luoma, Sotaniemi and Arranto, Scandinavian Journal of Clinical Laboratory Investigation (1983), 2739 utilizing antipyrine kinetics, evaluated the relationship between serum low-density and high-density lipoprotein-cholesterol and liver microsomal enzyme induction in thirty epileptics and thirty normal controls. All patients had been treated with PHT alone or in combination with phenobarbital and/or carbamazepine for at least two years. The treated patients had higher HDL-C levels and higher HDL-C to total-cholesterol ratios than control subjects. LDL/HDL-C ratio was reduced, indicating a cholesterol transfer from LDL to HDL. Serum total-cholesterol, LDL-C and triglycerides, however, were the same in both groups. The antipyrine clearance rate, which served as a measure of microsomal enzyme induction, was enhanced two-fold in the treated group, as compared to the controls.

2739. Luoma, P. V., Sotaniemi, E. A., Arranto, A. J., Serum LDL cholesterol, the LDL/HDL cholesterol ratio and liver microsomal enzyme induction evaluated by antipyrine kinetics, Scand. J. Clin. Lab. Invest., 43; 671-75, 1983.

Chalmers and Johnston, Journal of Neurology, Neurosurgery and Psychiatry (1983),2383 found that PHT (500 mg the evening prior to testing) increased exercise-induced free fatty acids, blood glycerol and total ketone concentrations. The authors suggest that PHT enhances lipid breakdown after exercise.

2383. Chalmers, R. J., Johnson, R. H., The effect of diphenylhydantoin on metabolic and growth hormones during and after exercise., J. Neurol. Neurosurg. Psychiatry, 46(7): 662-65, 1983.

Maguire, Murthy and Hall, European Journal of Pharmacology (1985),2737 reported that, in mice, administration of PHT and other hydantoins (20 mg/kg per day, intraperitoneally), for sixteen days, led to lower serum concentrations of cholesterol and triglycerides. The authors found that PHT and the other agents tested had significant hypolipidemic activity and were more effective than clofibrate in lowering serum cholesterol and triglycerides.

See also Clinical Cardiac section and Refs. 1968, 2282, 2319, 2323, 2652, 2732, 2733, 2741, 2742, 2946.

2737. Luoma, P. V., Reunanen, M. I., Sotaniemi, E. A., Changes in serum triglyceride and cholesterol levels during long-term phenytoin treatment for epilepsy, Acta Med. Scand., 206:229-31,1979.
1968. Luoma, P. V., Myllyla, V. V., Sotaniemi, E. A. and Hokkanen, T. E. J., Plasma HDL cholesterol in epileptics with elevated triglyceride and cholesterol, Acta Neurol. Scand., 60: 56-63, 1979.
2282. Allen, J. K., Whitfield, J. B., Hensley, W. J., The effects of diphenylhydantoin on the relationship between high-density lipoprotein cholesterol and several biochemical assays, Clin. Chim. Acta, 102: 111-14, 1980.
2319. Bell, H. H., Dittmeier, G. E., Increase in HDL2 cholesterol with phenytoin therapy, Arteriosclerosis, 5(5): 514A, 1985.
2323. Berlit, P., Krause, K. H., Heuck, C. C., Schellenberg, B., Serum lipids and anticonvulsants, Acta Neurol. Scand., 66: 328-34,1982.
2652. Kaukola, S., Manninen, V., Neuvonen, P. J., Malkonen, M., Ehnoholm, C., Effect of phenytoin on serum lipoproteins in middle-aged men, J. Cardiovasc. Pharmacol., 3: 207-14,1981.
2732. Luoma, P. V., Sotaniemi, E. A., Pelkonen, R. O., Arranto, A., Ehnholm, C., Plasma high-density lipoproteins and hepatic microsomal enzyme induction: relation to histological changes in the liver, Eur. J. Clin. Pharmacol., 23: 275-82, 1982.

2733. Luoma, P. V., Myllyla, V. V., Sotaniemi, E. A., Hokkanen, T. E., Plasma HDL cholesterol and growth hormone in epileptics treated with anticonvulsants, Acta Pharmacol. Toxicol., 47: 249-251, 1980.
2741. Luoma, P. V., Sotaniemi, E. A., Pelkonen, R. O., Savolainen, M. J., Arranto, A., Enholm, C., Enzyme-inducers reduce the risk of atherosclerotic vascular disease?, Br. J. Clin. Pharmacol., 14(4): 606P, 1982.
2742. Luoma, P. V., Sotaniemi, E. A., Pelkonen, R. O., Inverse relationship of serum LDL cholesterol and the LDL/HDL cholesterol ratio to liver microsomal enzyme induction in man, Res. Commun. Chem. Pathol. Pharmacol., 42(l): 173-6,1983.
2946. Serra, S., Callito, G., DeDomenico, P., Morgante, L., Bianchi, L., Ajello, L., Musolino, R., Arena, A., DiPerri, R., Influence of antiepileptic drugs on plasma lipid levels, Acta Neurol., 38(3): 190-7,1983.