Evaluations on New Drugs
Drugs 15: 409-428(1978 ) Q
ADIS Press 1978
Probucol : A Rev iew of its Pharmacological Properties and Therapeutic Use in Patients with Hypercholesterolaemia R.C. Heel, R.N . Brogden, T.M . Speight and G.s. A very Aust ralasian Drug Information Services, Auckland
Various sect ions of the manuscript reviewed by , S M. Grund y, Vel erans Adm inistration Hospital , La Jolla. California. USA; J .D.Hickie, University 01 New Soo th Wa~s. Kensington , Austra lia; RJ. Levy, National Heart, Lung. and Blood Institu le , Natiooal InstitLltes of Health . Bethesda. Mary land , USA ; B. Lew is. 5 1. Tnomas's Hospital Medical School, Londo n, England: P.1. Nesrel. Baker Medical Research Institute , Prllhran, Aust ralia; M E . Oliver. Royal lnlirma ry. Edinburgh. Scotlaod : A .J. Palmer . Prince Henry Hcspnal, Littl e Bay. Australia: P.J . Scott Univer sity of Auckland School of Medicintl. Auckland . New Zealand; R. Zelis, M ilton S. Hershey Med ical Cenler, Pennsylliania State Unive rsity. Hershey. Pennsytvania. USA.
Table of Coatems Summary 1. Pharmacodynam ic Stud ies 1.1 Lipid·Lowering Activity 1. 1 [ Effect on Serum CholClterol and Lipoprotein Le vels I 1.2 Effect On Serum Trigl yceride Levers 1.1.3 Mechanism of Action 1.2 Influence On Experim enta l Atherosclerosi s , 1.3 Safety Studies " 1.4 Toxicology Stud ies , 1.4. 1 Acute Toxicity 1.4.2 Subacute and Ch roni c Toxicity 1.4.3 Dysmorphology Studies . 2. Pharmacokinetic Studies . 2.1 Absorption and Plasma Level Profile 2.2 Distribution and Metabo lism 2.3 Elimination 3. Therapeutic T rials . 3. 1 Controlled Tri als
4 10 .
4 12 4 12
-u
4IJ
. .
414 414 414
m
415 415 415 ' 15
m
'16
41 ' 4 16
417
Probucol: A Review
410
3.1.1 Comparisons with a Placebo 3.1.2Comparisons with Oo f,brate . 3.1,3 Combined Use with Other Lipid-Lowering Drugs 3.2 Open Trials . 3.3 Factors Affecting the Response10 Probuccl 3.4 The Place of Probucol in Treating Hyperlipidaemias . 4. Side-Effecu. 5. Dosage and Admi nistration
Su mmary
'" '"
421 421 425
426 426
416
Syn opsis : Probuco!' is a chdesterot-lowertng drug wi/hou / structural similarilies to orher lipid-lo wering agents, It reduces serum cholcuerot tevett by aboul 10 10 15 % in mosr patients with hypercholesterolaemia . but does no/ appear 10 lower serum triglyceride levels, and thus would seem 10 be useful primarily in patients with hyperchotestercloemia alone (type tla hv pertiooproteinaemia]. Comparative studies with bile acid -binding resins. "'hich are also useful in type l1a patients, have nor been done. Probucol's effec/ on the serum concentrations of lipoprotein cholesterol frac tions needs /0 be f urther clarified in addi/ional studies. bur n ap pears to mainly lower low density lipoprotein cholesterol levels. In all studies in ma n reported thus f ar proburol has been well tolerated. only a few patients discontinuing treatmen t due /0 side-effects. 11 is given in tablet fo rm in a twice daily dose , li s relative ease 0/ adminislrarion compared with bile acid-binding resins , if accompanied by equivalent effectiveness. would offer a considerable ad vantage in Q group of patienn in whom drug therapy. once begun. is usually continued/or a lorrg period; but whether or not prooucot is as effective as these agents has not been demonstrated in comparative studies.
Pharmacodynamic studies: Additio n of probuool to the diet of rats and mice reduced serum cholesterol levels without changing liver cholestero l concentrations, unli ke clofibrate and cotesnpot (other lipid-lowe ring drugs) which reduced liver cholesterol. In stud ies in volunteers with high normal o r moderately elevated serum cholesterol levels, receiving their regula r diet, 375 to 3000mg of pro buco l daily for 6 weeks lowered serum cho lesterol levels by about 30 96 ; although in therapeutic trial s (see section ) the response was usu ally less, Increasing the dose beyond 750mg daily to )OOOmg per day did not produce a signi ficantl y greater response in volunteers. Twice daily dose s we re more effective than a single dai ly dose. The mechanism of probucol's cholesterol-loweri ng activity has not been clearly dem o nstrated, but som e authors have suggested that inhi bition of lipoprotein formation and / or impaired intes tinal mucosal transport of cholesterol ma y be invo lved. Pharmacoki netic studies: The re is little publis hed info rmation on the pharmacokinetic properties of probucol in man . Largely from unpub lished information it appea rs that absorpt ion after oral administration of single doses is limited and variable. During chro nic administratio n plasma levels increase grad ually , reac hing a steady sta te after ) to 4 months of treatment. In animal studies probucol was retained in adipose tissue, the concentrati on in body fat being 100 times that in the plasma after 2 years of administration to monkeys. In rats and dog s th e bile was a majo r rou te of elimination of probuco t after a single mcavenous dose . In man abo ut 80 % of a single radioactive dose, administered 10 patients who had received Ig of
'Loreloo' ( Dow).
probucct
A
Revlew
Drugs 15: 409-428(1978 ) Q
ADIS Press 1978
Probucol : A Rev iew of its Pharmacological Properties and Therapeutic Use in Patients with Hypercholesterolaemia R.C. Heel, R.N . Brogden, T.M . Speight and G.s. A very Aust ralasian Drug Information Services, Auckland
Various sect ions of the manuscript reviewed by , S M. Grund y, Vel erans Adm inistration Hospital , La Jolla. California. USA; J .D.Hickie, University 01 New Soo th Wa~s. Kensington , Austra lia; RJ. Levy, National Heart, Lung. and Blood Institu le , Natiooal InstitLltes of Health . Bethesda. Mary land , USA ; B. Lew is. 5 1. Tnomas's Hospital Medical School, Londo n, England: P.1. Nesrel. Baker Medical Research Institute , Prllhran, Aust ralia; M E . Oliver. Royal lnlirma ry. Edinburgh. Scotlaod : A .J. Palmer . Prince Henry Hcspnal, Littl e Bay. Australia: P.J . Scott Univer sity of Auckland School of Medicintl. Auckland . New Zealand; R. Zelis, M ilton S. Hershey Med ical Cenler, Pennsylliania State Unive rsity. Hershey. Pennsytvania. USA.
Table of Coatems Summary 1. Pharmacodynam ic Stud ies 1.1 Lipid·Lowering Activity 1. 1 [ Effect on Serum CholClterol and Lipoprotein Le vels I 1.2 Effect On Serum Trigl yceride Levers 1.1.3 Mechanism of Action 1.2 Influence On Experim enta l Atherosclerosi s , 1.3 Safety Studies " 1.4 Toxicology Stud ies , 1.4. 1 Acute Toxicity 1.4.2 Subacute and Ch roni c Toxicity 1.4.3 Dysmorphology Studies . 2. Pharmacokinetic Studies . 2.1 Absorption and Plasma Level Profile 2.2 Distribution and Metabo lism 2.3 Elimination 3. Therapeutic T rials . 3. 1 Controlled Tri als
4 10 .
4 12 4 12
-u
4IJ
. .
414 414 414
m
415 415 415 ' 15
m
'16
41 ' 4 16
417
Probucol: A Review
410
3.1.1 Comparisons with a Placebo 3.1.2Comparisons with Oo f,brate . 3.1,3 Combined Use with Other Lipid-Lowering Drugs 3.2 Open Trials . 3.3 Factors Affecting the Response10 Probuccl 3.4 The Place of Probucol in Treating Hyperlipidaemias . 4. Side-Effecu. 5. Dosage and Admi nistration
Su mmary
'" '"
421 421 425
426 426
416
Syn opsis : Probuco!' is a chdesterot-lowertng drug wi/hou / structural similarilies to orher lipid-lo wering agents, It reduces serum cholcuerot tevett by aboul 10 10 15 % in mosr patients with hypercholesterolaemia . but does no/ appear 10 lower serum triglyceride levels, and thus would seem 10 be useful primarily in patients with hyperchotestercloemia alone (type tla hv pertiooproteinaemia]. Comparative studies with bile acid -binding resins. "'hich are also useful in type l1a patients, have nor been done. Probucol's effec/ on the serum concentrations of lipoprotein cholesterol frac tions needs /0 be f urther clarified in addi/ional studies. bur n ap pears to mainly lower low density lipoprotein cholesterol levels. In all studies in ma n reported thus f ar proburol has been well tolerated. only a few patients discontinuing treatmen t due /0 side-effects. 11 is given in tablet fo rm in a twice daily dose , li s relative ease 0/ adminislrarion compared with bile acid-binding resins , if accompanied by equivalent effectiveness. would offer a considerable ad vantage in Q group of patienn in whom drug therapy. once begun. is usually continued/or a lorrg period; but whether or not prooucot is as effective as these agents has not been demonstrated in comparative studies.
Pharmacodynamic studies: Additio n of probuool to the diet of rats and mice reduced serum cholesterol levels without changing liver cholestero l concentrations, unli ke clofibrate and cotesnpot (other lipid-lowe ring drugs) which reduced liver cholesterol. In stud ies in volunteers with high normal o r moderately elevated serum cholesterol levels, receiving their regula r diet, 375 to 3000mg of pro buco l daily for 6 weeks lowered serum cho lesterol levels by about 30 96 ; although in therapeutic trial s (see section ) the response was usu ally less, Increasing the dose beyond 750mg daily to )OOOmg per day did not produce a signi ficantl y greater response in volunteers. Twice daily dose s we re more effective than a single dai ly dose. The mechanism of probucol's cholesterol-loweri ng activity has not been clearly dem o nstrated, but som e authors have suggested that inhi bition of lipoprotein formation and / or impaired intes tinal mucosal transport of cholesterol ma y be invo lved. Pharmacoki netic studies: The re is little publis hed info rmation on the pharmacokinetic properties of probucol in man . Largely from unpub lished information it appea rs that absorpt ion after oral administration of single doses is limited and variable. During chro nic administratio n plasma levels increase grad ually , reac hing a steady sta te after ) to 4 months of treatment. In animal studies probucol was retained in adipose tissue, the concentrati on in body fat being 100 times that in the plasma after 2 years of administration to monkeys. In rats and dog s th e bile was a majo r rou te of elimination of probuco t after a single mcavenous dose . In man abo ut 80 % of a single radioactive dose, administered 10 patients who had received Ig of
'Loreloo' ( Dow).
probucct
A
Revlew
