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| Pronunciation | /ˈproʊbjukɒl/ PROH-bew-kol |
| Trade names | Lorelco |
| Other names | 2,6-di-tert-butyl-4-({2-[(3,5-di-tert-butyl-4-hydroxyphenyl)sulfanyl]propan-2-yl}sulfanyl)phenol |
| AHFS/Drugs.com | Micromedex Detailed Consumer Information |
| MedlinePlus | a611037 |
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| Pharmacokinetic data | |
| Metabolism | minimally renal[1][2] |
| Eliminationhalf-life | 50-62 h initial, 98 h steady-state[1][2] |
| Excretion | fecal (84%), urinary (1.9%)[1][2] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.041.404 |
| Chemical and physical data | |
| Formula | C31H48O2S2 |
| Molar mass | 516.84 g·mol−1 |
| 3D model (JSmol) | |
| Solubility in water | very soluble in tricholoromethane, soluble in ethanol, insoluble in water[3] |
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Probucol, sold under the trade nameLorelco among others, is anlipid-lowering agent[4] initially developed for the treatment ofcoronary artery disease. Clinical use was discontinued in some countries after it was found that the drug may have the undesired effect of loweringHDL-C in patients with a previous history of heart disease.[5][6] It may also causeQT interval prolongation.[6][7]
Probucol was originally developed as an industrial antioxidant added to tires to maximize their longevity.[8]
In Japan, it is approved for "hyperlipidemia (includingfamilial hypercholesterolemia andxanthomas)".[1][2] In China, it is approved for hypercholesterolemia.[9]
During both clinical trials and postmarketing surveillance, most adverse effects were limited to the digestive system and the skin. Those included diarrhea, abdominal pain, nausea, loss of appetite, rash, and itching. For each of these effect, the incidence was between 0.1% and 1% ("uncommon"). QT prolongation was noted as rare (< 0.1%) in the package inserts. Elevated liver enzymes (ALT, AST, ALP, LDH), elevated BUN, reduction in red blood cells, white blood cells, and/or platelet count, elevatedcreatine kinase are also possible.[1][2] The Chinese package insert states that ALT, AST, bilirubin, uric acid, and BUN elevations are transient.[9]
Possible serious adverse effects include ventricular arrhythmia (Torsades de pointes), syncope, gastrointestinal bleeding, peripheral neuritis, and rhabdomyolysis. The frequency of these are unknown.[1][2]
May reduce the blood concentration ofcyclosporin (unknown mechanism). There exist reports of significantly declined HDL-C withclofibrate (unknown mechanism).[1]
Risk of arrhythmia is elevated when used with other drugs that can cause arrhythmia, especiallytricyclic antidepressants andphenothiazines.[9] Potentiates the effect of diabetic medications and coumarin anticoagulants.[9]
Probucol lowers the level ofcholesterol in the bloodstream by increasing the rate ofLDLcatabolism. Specifically, this happens by changing the structure of LDL, among other effects. TheLDL receptor is not involved: it works in rabbits and humans without a working LDL receptor (homozygousfamilial hypercholesterolemia).[5] It also enhances the excretion of cholesterol into bile. It is able to lower LDL-C by 10-20%.[5]
It is also a powerfulantioxidant. At a low dose (insufficient to affect LDL-C or HDL-C levels), it prevents the oxidation of cholestrol in LDLs.[5] This might slow the formation offoam cells, which formatheroscleroticplaques. It partially does this by increasingPON1 activity, thus increasing the antioxidant properties of HDL.[5][10]
Probucol also lowers HDL-C (HDL cholesterol, i.e. the amount of cholesterol found in HDLs) by about 30%. This has historically caused its discontinuation from several Western countries.[5] This has several causes:
Recall that one of the functions of HDL isreverse cholesterol transport (moving cholesterol from peripheral tissues into the liver). Inhibition of ABCA1 would be detrimental to the process, whereas enhancing CETP and SR-BI activities is beneficial for the transport function. Overall, probucol increases the capacity for reverse cholesterol transport, so the observed HDL-C reduction does not lead to a decrease in a patient's cholesterol-removing ability.[5]
The adverse effect of QT prolongation is possibly due to inhibition ofhERG trafficking.[7]
Oral absorption is limited and erratic. Food increases absorption. With a single oral dose of 250 mg, tmax is at 18 hours post-ingestion.[1] If taken daily, 3 to 4 months are required to reach steady-state concentrations.[9]
The tissue distribution of probucol has been studied in rats, dogs, and monkeys using a14C-labelled version of the drug. In rats, a single 100 mg/kg dose results in liver, adrenal glands, and brown fat concentrations at 3–10× plasma concentration and central nervous system, gonad, and eye concentrations at 1/7–1/20× plasma concentration. In rats, 21 days of continuous 100 mg/kg/d feeding results in accumulation in brown fat, adrenal glands, liver, and adipose tissue at 10–46× plasma concentration and central nervous system, gonad, and eye concentrations at 1–1/2× plasma concentration.[1]
Probucol has been found to have antioxidant and anti-inflammatory properties via several different mechanisms.[14] These properties have led to research into the drug's potential capacity to treatsensorineural hearing loss related tooxidative stress,[14][15] as well as formulations to improve the delivery of the drug into the ear.[15]
After promising test results in mouse models, probucol is under study at Weston Brain Institute of McGill University as a possible aid in delaying the onset ofAlzheimer's disease.[citation needed] The protocol for a future Australian Phase II study was published in 2022.[16]
Novel packaging methods have been tried to optimize the pharmacokinetic properties of probucol – the goal is usually to produce a more stable absorption profile and to reduce absorption bycardiac muscle cells. Some show promise in lab animals, but have not yet been tested in humans.[17]
A number of probucol analogues have been tested in animal models by researchers seeking to optimize aspects of probucol's action while reducing its side effects. Succinobucol, the succinate ester of probucol, failed to demonstrate a useful degree of efficacy in clinical trials targeting acute coronary syndrome. BO-653, another analogue, failed its phase II trial targeting atherosclerosis treatment and prevention of post-angioplasty restenosis.[17]
In Japan, Probucol was available under both the Lorelco brand name, the Sinlestal brand name, and the generic "TOWA" brand. In January 2021, Towa Pharmaceutical Co., Ltd. announced that it would discontinue the sale of Probucol Tablets 250 mg "TOWA" due to various circumstances.[18]
Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C).
Probucol was developed as an anti-oxidative compound to prevent the degradation of tire rubber and later applied to reduce serum LDL-C levels in patients with hypercholesterolemia.
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