Probucol: A Review of its Pharmacological Properties and Therapeutic Use in Patients with Hypercholesterolaemia

Summary

Synopsis: Probucol¹ is a cholesterol-lowering drug without structural similarities to other lipid-lowering agents. It reduces serum cholesterol levels by about 10 to 15% in most patients with hypercholesterolaemia, but does not appear to lower serum triglyceride levels, and thus would seem to be useful primarily in patients with hypercholesterolaemia alone (type Ha hyperlipoproteinaemia). Comparative studies with bile acid-binding resins, which are also useful in type IIa patients, have not been done. Probucol’s effect on the serum concentrations of lipoprotein cholesterol fractions needs to be further clarified in additional studies, but it appears to mainly lower low density lipoprotein cholesterol levels.

In all studies in man reported thus far probucol has been well tolerated, only a few patients discontinuing treatment due to side-effects. It is given in tablet form in a twice daily dose. Its relative ease of administration compared with bile acid-binding resins, if accompanied by equivalent effectiveness, would offer a considerable advantage in a group of patients in whom drug therapy, once begun, is usually continued for a long period; but whether or not probucol is as effective as these agents has not been demonstrated in comparative studies.

Pharmacodynamic studies: Addition of probucol to the diet of rats and mice reduced serum cholesterol levels without changing liver cholesterol concentrations, unlike clofibrate and colestipol (other lipid-lowering. drugs) which reduced liver cholesterol. In studies in volunteers with high normal or moderately elevated serum cholesterol levels, receiving their regular diet, 375 to 3000mg of probucol daily for 6 weeks lowered serum cholesterol levels by about 30%; although in therapeutic trials (see section 3) the response was usually less. Increasing the dose beyond 750mg daily to 3000mg per day did not produce a significantly greater response in volunteers. Twice daily doses were more effective than a single daily dose. The mechanism of probucol’s cholesterol-lowering activity has not been clearly demonstrated, but some authors have suggested that inhibition of lipoprotein formation and/or impaired intestinal mucosal transport of cholesterol may be involved.

Pharmacokinetic studies: There is little published information on the pharmacokinetic properties of probucol in man. Largely from unpublished information it appears that absorption after oral administration of single doses is limited and variable. During chronic administration plasma levels increase gradually, reaching a steady state after 3 to 4 months of treatment. In animal studies probucol was retained in adipose tissue, the concentration in body fat being 100 times that in the plasma after 2 years of administration to monkeys. In rats and dogs the bile was a major route of elimination of probucol after a single intravenous dose. In man about 80% of a single radioactive dose, administered to patients who had received 1g of probucol daily for 3 weeks, was excreted in the faeces in the first 4 days after administration, but some radioactivity was still detectable in the plasma after 50 days. At 6 weeks and at 6 months after discontinuing probucol in 8 patients who had received 1g of probucol daily for 1 year, plasma levels had decreased by only 60% and 80%, respectively.

Therapeutic trials: Probucol has been studied in a reasonably large number of patients in open trials and in a smaller number of patients in placebo-controlled studies. Like the bile acid-binding resins (cholestyramine, colestipol), probucol appears to be primarily useful in patients with hypercholesterolaemia alone (type IIa hyperlipoproteinaemia), but comparative studies with these agents have not been reported.

In most studies probucol usually lowered serum cholesterol levels by about 10 to 15% (although some patients, especially with severe primary hypercholesterolaemia, have failed to respond), the maximum effect occurring after 1 to 3 months of administration. Serum cholesterol levels have been lowered by about the same extent in patients with hypercholesterolaemia alone and in patients with mixed hypercholesterolaemia and hypertriglyceridaemia. In the best designed controlled trial, probucol reduced serum cholesterol levels 13% more than could be achieved by diet alone in 30 patients with familial (type Ha or IIb) hypercholesterolaemia, while a placebo did not improve the response achieved with a fat-restricted diet alone. Although both high density and low density lipoprotein cholesterol were reduced in this study, the low density fraction accounted for most of the total serum cholesterol decrease. Additional studies are required to further clarify the drug’s effect on serum lipoprotein cholesterol fractions.

There have been variable changes in serum triglyceride levels during probucol administration in therapeutic trials. Thus, triglyceride concentrations have markedly decreased in a few patients with very high (600 to 3000mg/100ml) pretreatment levels, but conversely large increases in triglyceride levels have occasionally occurred (Nash, 1975). In most patients however, there has either been no change, or only a slight increase or decrease.

Side-effects: Although the number of long-term studies is limited, in short term trials and in a smaller number of patients treated for several years probucol has been well tolerated. Only a few patients have discontinued treatment due to side-effects. The most common adverse reaction has been diarrhoea (or loose stools), the reported incidence of which has varied widely in therapeutic trials (from 2 to 30%). Other gastrointestinal symptoms such as flatulence, nausea, and abdominal pain have also been reported. An idiosyncratic reaction characterised by dizziness and palpitations in 1 patient has been observed. 2 studies have reported mild, transient eosinbphilia in 10 to 30% of patients.

Dosage and administration: Like other lipid-lowering drugs, probucol should be used only as a supplement to other appropriate therapeutic rneasures, such as diet and attempted reduction to ideal weight, or treatment of an underlying cause of hypercholesterolaemia to reduce serum cholesterol levels; and only when appropriate dietary regimens alone have been proven inadequate. Although it may lower elevated cholesterol levels in patients with mixed hyperlipidaemia (hypercholesterolaemia with hypertriglyceridaemia), it is not intended for use when hypertriglyceridaemia is the primary concern.

The recommended adult dosage is 500mg twice daily taken with the morning and evening meals. Adequate baseline studies of both serum cholesterol and triglyceride levels should be performed to facilitate periodic monitoring during drug administration. A favourable trend in cholesterol serum levels should occur in the first 2 months of treatment, but subsequent periodic monitoring of cholesterol levels should also be undertaken to determine if the drug remains effective over longer periods. Probucol should be discontinued if a persistent, marked rise in serum triglyceride levels which does not respond to restricted alcohol intake and other appropriate dietary measures occurs.