Transportation of LipidsLipoproteins serve to transport lipids from tissue to tissue and participate in lipid metabolism.

They consist of proteins and lipids and can be grouped into various categories based on their density.

The inside of the particles has varying amounts of neutral lipids cholesterol esters and triacylglycerols.

The surrounding shell is made up of amphoteric phospholipids, free cholesterol, and apolipoproteins (purified protein components of a lipoprotein particle).

This surrounding shell allows the transport of the lipoproteins through the aqueous plasma.

Generalized structure for the plasma lipoproteins:Spherical particle consisting of a core of triglycerides and cholesterol esters with a shell 20-Angstroms thick of apolipoproteins, phospholipids, and unesterified cholesterol. Apolipoproteins are embedded with their hydrophobic edges oriented toward the core and their hydrophilic edges toward the outside.

There are 5 major classes of lipoproteins that have specific physiological and anatomical significance.

They are secreted in one form and rapidly transformed to others by interaction with specific enzymes such as:lecithin cholesterol acyltransferase (LCAT),lipoprotein lipase (LPL),hepatic triglyceride lipase (HTGL),and other lipoproteins.

Apoliproteins are protein constituents of the lipoprotein, that can activate enzymes or act as a ligand for binding to cell receptors.

E and B-48 ligands for LRP

CII and E stimulate lipase

Main Function:Transports dietary lipidsto sites of use or storage

Chylomicrons are the largest particles of low density. They are synthesized from fat in the intestine, enter the blood, and transport triglycerides and cholesterol to the periphery or extrahepatic tissues. Lipoprotein lipase removes triglycerides in the extrahepatic tissues leaving chylomicron remnants to be taken up by LDL receptor related protein (LRP) on the liver, for conversion of chylomicron remnants to VLDL, IDL and LDL. Main function of chylomicrons is to transport dietary lipids to

tissues for use and storage.

VLDL (Very-Low-Density-Lipoprotein) is synthesized in the liver and have a half-life of about 12 hours. They function to transport free fatty acids from the liver to peripheral tissues. On the tissue surface LPL hydrolyzes the triglycerides for transport into the tissues. The rest of the VLDL lipoprotein interacts with HDL to obtain more Apo C and more Apo E eventually forming IDL a precursor for LDL. High levels of VLDL (triglycerides > 1000 mg/dl) indicate a risk for pancreatitis.

Recognize LDL receptors on liver and tissues

IDL (Intermediate-Low Density Lipoprotein) are formed from the LPL hydrolysis of triglycerides from VLDL. They are either taken up by the liver via LDL receptors or converted to LDL lipoproteins. IDL functions mainly as an intermediate for the synthesis of LDL

(remnant)

LDL (Low-Density-Lipoprotein) has a half-life of about 3 days and is synthesized from IDL. They contain about 65% cholesterol and transport the cholesterol from the blood to both the liver and extra-hepatic tissues. The major apolipoprotein is Apo B-100 which is recognized by the LDL surface receptor in the liver and extrahepatic tissues. High levels are bad. Main function is to deliver cholesterol to extra-hepatic tissues.

Nascent HDL (High-Density Lipoprotein) is synthesized in the liver and intestine forming phospholipid discs containing Apo A-1. AI is recognized by a scavenger receptor (SR-BI) on the liver thus taking HDL into the liver. High levels are good. Main function is to transport cholesterol from tissues back to liver thus HDL is a scavenger for cholesterol.

Summary of the separate metabolic pathways

for the degradation of exogenous (dietary)

lipoproteins and endogenous lipoproteins

formed by hepatic metabolism.

FCHL: Familial combined hyperlipidemiaFHTG:Familial hypertriglyceridemiaRRD: Remnant removal disease or familial dysbetalipoproteinemiaLRP: LDL receptor-related proteinFH: Familial hypercholesterolemia increased LDL

Increase triglyceride and VLDL

Increase LDL and VLDL

IDL

Low HDL

VLDL

Role of Oxidized LDL-cholesterol in the development of atherosclerosis:

LDLs are transported from the arterial lumen into endothelial cells and into the space that underlies the arterial epithelium.

Alternatively an injury can attract the LDL-cholesterol and platelets.

Underneath the arterial epithelium, LDLs are oxidized specifically taken up by scavenger receptors of macrophages to start the process of atherosclerosis.

Development of an atherosclerotic lesion

Summary of Lipoproteins

Lipoprotein Class*

Major Core Lipids Apolipoproteins Transport FunctionInfluence on

Atherosclerosis

VLDL Triglycerides B-100, E, othersDelivery of triglycerides to nonhepatic tissues

Probably contribute to atherosclerosis

LDL Cholesterol B-100Delivery of cholesterol to nonhepatic tissues

Definitely contribute to atherosclerosis

HDL Cholesterol A-I, A-II, A-IV

Transport of cholesterol from nonhepatic tissues back to the liver

Protect against atherosclerosis

*VLDL = very low density lipoproteins; LDL= low density lipoproteins; HDL = high density lipoproteins

Classification of Cholesterol Concentrations (AHA)

Total Blood Cholesterol

>200 mg/dl Desirable

200-239 mg/dl Borderline risk

≥ 240 mg/dl High risk

LDL Cholesterol (Blood)

<100 mg/dl Desirable

100-130 mg/dl Borderline risk

≥ 130 mg/dl High risk

HDL cholesterol (Blood)

>40 mg/dl (men)

>50 mg/dl (women)

Desirable

Desirable

Newer “margarines” are derived from

soy or pine oil and lower LDLs

Health Risks Triglycerides LDL HDL CAD

high weight + + - +

smoking   + - +

margarine + + -  

trans F.A. + +    

hypertension   +   +

diabetes + +   +

exercise - - + -

Drugs for Treatment of Hyperlipidemia

Niacin (Nicotinic acid)

Fibric Acids

Bile acid-binding Resins

Statins

Weight loss and Dietary Management should be tried first

Ezetimibe

Chemistry and Pharmacokinetics:

Water soluble vitamin B3 that is incorporated into niacinamide adenine dinucleotide (NAD) and is excreted in the urine. Nicotinamide itself has no antilipemic activity.

Mechanisms of Action of Nicotinic Acid. The mobilization of free fatty acids (FFA) from peripheral adipose tissue to the liver is inhibited by nicotinic acid resulting in a decrease in the synthesis of VLDL and ultimately to a decrease in low-density lipoprotein (LDL). Nicotinic acid increases serum HDL cholesterol concentrations by up to 30 percent by reducing the clearance of apoA-I lipoprotein by the liver resulting in higher apoA-I concentrations and an increase HDL levels .

Overall Effect:Decreases VLDL and LDL and triglycerides.

Reduces LDL by 15 to 35% and triglyceridesby 30% to 45%. HDL rises by 25% to 35%.

Most effective when given in combination with other drugs.

If a bile acid-binding resin is added 40 to 60% reduction in LDL: in triple therapy with bile acid-binding resin plus a statin it decreases LDL by 70% or more.

Drug of choice for lowering VLDL levelsin patients at risk of pancreatitis, and for mixed elevations of LDLs and VLDLs and low levels of HDLs.

Very effective in increasing levels of HDL, and is given orally with meals from 1.5 to 6.5 g per day. (Taken as a vitamin at 25 mg/day)

Side Effects and Contraindications

Dyspepsia, skin flushing , itching (prostaglandin mediated effect—controlled by aspirin)

Hepatotoxicity is less likely with extended release formulas.

Contraindications: Cardiac atrial arrhythmias, peptic ulcers, gout (↑ uric acid levels) and diabetes, and gallbladder disease.

Combination statin therapy: ↑ risk of myopathy or rhabdomyolysis.

Fibric Acid Derivatives: Gemfibrozil, Fenofibrate

1. Enhance oxidation of FA in liver and muscle.

2. Reduce rate of lipogenesis in liver.3. Increased synthesis of Apo AI &II for more HDL

PPARα activator—peroxisome proliferator activated receptors

Summary:

Fibrates activate nuclear transcription factors, peroxisome proliferators activated receptor-alpha (PPAR-alpha), which regulate genes that control lipid metabolism.

Chemistry and Pharmacokinetics

Gemfibrozil is derived from the first-generation drug clofibrate.

Fibrates are free carboxylic acids and tightly bound to plasma proteins.

They are eliminated as glucuronide conjugates through the kidney.

Fenofibrate may lower LDL more effectively than gemfibrozil with fewer drug-drug interactions than statins.

Therapeutic Use:

Decreases triglyceride (VLDL) levels and raises HDL-cholesterol levels.

It has varying effects on LDL-cholesterol.

Principle indication for all fibrates is elevation of plasma triglycerides (VLDLs).

Adverse Effects:GI (nausea, diarrhea, abdominal pain),

hepatotoxic, gallstones.

Displaces warfarin so measure prothrombin time.Increases risk of statin-induced myopathy (esp. gemfibrozil inhibits the glucuronidation of statins). Contraindicated for patients with pre-existing gallstones. Avoid in patients with renal failure, hepatic dysfunction, preexisting gall bladder conditions and hypersensitivity.

DrugDose Range Plasma half-life Metabolism Excretion

Bezafibrate200 mg three times a day or 400 mg daily as sustained-release preparation

2 hrGlucuronidation.  50% remains unchanged

Renal

Ciprofibrate 100 mg daily 42 hr Glucuronidation Renal

Fenofibrate100 mg three time a day or 200 mg daily as micronised preparation

20-27 hrHydroxylation converts parent compound to active metabolite

Renal

Gemfibrozil 300-1200 mg ~8 hr Conjugation Renal

Clofibrate 500-2000 mg 13-25 hr Glucuronidation Renal

Pharmacokinetic Properties of the Fibrates

Bile Acid-Binding ResinsCholestyramine, Colestipol and

Colesevelam

Chemistry and Pharmacokinetics:

Large polymeric cationic exchange resinsthat are insoluble in water.

Chloride ion is released from the cationic quaternary ammonium binding site in exchange for bile acids.

Mechanism of Action:

Resins

Mechanism of Action:

Following ingestion, the resins form an insoluble complex with bile acids present in the intestine thus preventing the reabsorption of bile acids.

This increased excretion creates a demand for more cholesterol to make more bile in the liver.

As a result more LDL receptors are made to endocytose more LDLs and increase the amount of LDL and cholesterol absorbed by the liver, decreasing plasma LDL levels.

Therapeutic Use:

Lowering elevated levels of LDL-cholesterol (15% to 20% reduction) particularly in combination with statins.

The addition of nicotinic acid (50% reduction) and statin and resin (40 to 45%).

Safe since not absorbed, mixed with fruit juice and a lot of water

Adverse Effects:

cholestyramine and colestipol, colesevelam all slightly increase triglyceride synthesis (contraindicated for severe hypertriglyceridemia)

cholestyramine and colestipol: constipation bloating, indigestion, nausea, decrease the uptake of fat soluble vitamins (A, D, E, and K), and drugs like warfarin, statins and folic acid.(give drugs or vitamins 1 hour before or 4 hours after to minimize)

Colesevelam—(Pill) fewer GI effects and does not interfere with absorption of other vitamins or drugs.

Adverse Effects (cont’d)

HMG CoA Reductase Inhibitors: Statins

Lovastatin Fluvastatin Pravastatin Simvastatin Atorvastatin

Rosuvastatin

Most effective drugs with few side effects

Atorvastatin (Lipitor)

Pravastatin(Pravachol)

Fluvastatin(Lescol)

Simvastatin(Zocor)

Lovastatin(Mevacor)

Structures resemble HMG

CoA

Rosuvastatin (Crestor)

Mechanism of Action:

Structural analogs of hydroxy-methylglutaryl-coenzyme A, a precursor of cholesterol and are competitive inhibitors of hepatic HMG CoAreductase, the rate-limiting enzyme in cholesterol biosynthesis.

Inhibition of HMG-CoA reductase by statin drugs

Decrease of cholesterol synthesis in the liver.

Reduction of serum cholesterol level due to synthesis of more LDL receptors, lowering LDL serum levels

VLDL and IDL removal occurs via the ApoE component recognition by LDL receptors.

These drugs also reduce inflammation by an unknown mechanism, particularly reducing the C-reactive protein, which is another indicator of risk for CAD.

Mechanism of Action:

Chemistry and Pharmacokinetics:

Lovastatin and simvastatin are inactive lactoneprodrugs that must be hydrolyzed to the activebeta-hydroxyl derivatives.

Atorvastatin, pravastatin, rosuvastatin, and fluvastatin are active drugs.

Rosuvastatin and simvastatin increase HDLs but less than niacin does.

All reductase inhibitors have a high first pass extraction by the liver.

Atorvastatin, simvastatin, and lovastatin metabolism is inhibited by a number of drugs: azole-antifungal, erythromycin, clarithromycin, cyclosporine, calcium channel blockers (verapamil and diltiazem), ritonavir, or grapefruit juice-which all inhibit cytochrome P450 enzymes—CYP3A4

Drug-drug interactions

Rifampin would accelerate the hydrolysis of the above drugs. Why?

Drug-drug interactions-cont’dFluvastatin is metabolized by CYP2C9 and rosuvasatin is only metabolized to a small extent by CYP2C9. Both drugs have fewer drug interactions.

Pravastatin is not metabolized by the cytochrome system and would not be affected by inducers or inhibitors of the cytochrome P450 system.

Rosuvastatin has reached higher than normal levels in Asian patients— caution warranted

Therapeutic Use:Major types of hyperlipidemia (lower LDL-cholesterol - 20% to 55%) and hypertriglyceridemia.

Some statins are given at night since cholesterol synthesis increases at night. Rosuvastatin and atorvastatin have long half-lives and so can be given at any time of day.

cholestyramine or colestipol + statins reduce levels 20 - 25% more.

Drug withdrawal returns LDL to previous levels. Statins may lower risk of colon cancer and osteoporosis.

Adverse Effects:

Headache, rash, GI disturbances (flatulence, cramps, constipation, abdominal pain), more severe but rare are hepatotoxicity, and myopathy. Myopathy especially with statins + gemfibrozil, fenofibrate or niacin.

None of these drugs should be given during pregnancy, as they have been found to be teratogenic in rodents.

Patient Therapy

Patients may tolerate one statin better than the other as well as different combinations of drugs

Most statins lower LDLs 30-40% but greater than 40% decrease occurs with atorvastatin, simvastatin and rosuvastatin.

Characteristic Atorvastatin*(Lipitor)

Fluvastatin(Lescol XL)

Lovastatin*(Mevacor)

Pravastatin(Pravachol)

Rosuvastatin(Crestor)

Simvastain *(Zocor)

Maximal Dose (mg/day)

80 mg/daybedtime

80 mg/daybedtime

80 mg/daybedtime

80 mg/daybedtime

40 mg/daybedtime

80 mg/daybedtime

Plasma half life 14 hr 2-3 hr 3-4 hr 2 hr 20 hr 3 hr

Max % Decrease TG

53% 25% 27% 24% 43% 38%

Max % Decrease LDL

60% 38% 40% 41% 63% 51%

Max % Increase HDL

14% 11% 13% 14% 22% 16%

Food Effect None None With meals None None None

Penetration CNS No No Yes No No Yes

Renal excretion 2% <6% 10% 20% 28% 13%

Hepatic Metabolism

CYP450 3A4 (less than lovastatin and simvastatin)

CYP450 2C9

CYP450 3A4

Sulfation CYP450 2C9 (minimal)Lower dosage for Asianpatients

CYP450 3A4

*CYP3A4 inhibitors raise statin levels, i.e. itraconazole erythromycin, clarithromycin HIV protease inhibitors, cyclosporine, grapefruit juice CYP3A4 inducer lower statin levels, i.e. rifampin, phenytoin, barbiturates

* * *

**

*CYP3A4 inhibitors raise statin levels, i.e. itraconazole erythromycin,

clarithromycin HIV protease

inhibitors, cyclosporine, grapefruit juice

CYP3A4 inducer lower statin levels, i.e. rifampin, phenytoin, barbiturates

Cholesterol Absorption Inhibitor

Newest Drug: Ezetimibe

Mechanism of Action: Selectively inhibits intestinal absorption of dietary and biliary cholesterol at the brush border of the small intestine.

Cholesterol levels are reduced in the liver and LDL-receptors increase on hepatocytes decreasing plasma LDLs

Mechanism of Action

After oral administration it is extensively converted to a pharmacologically active glucuronide in the small intestine and liver, and is excreted mostly in the stool.

Ezetimibe

In monotherapy it lowers LDL cholesterol by 17%, triglycerides by 6%, and increased HDL cholesterol by 1.3%.

It is not metabolized by the CYP450 enzymes

Side Effects

Well tolerated in contrast to bile acid binding resins.

Contraindicated for patients with moderate to severe hepatoxicity or gall bladder disease.

Cholestyramine and colestipol interfere with absorption of ezetimibe and so must be taken separately.

Combination Therapy Examples

Statin + Nicotinic Acid

Statin + Bile Acid Resin

Statin + Ezetimibe

Statin + Bile Acid Resin +Nicotinic Acid

Nicotinic Acid + Ezetimibe

Nicotinic Acid + Bile Acid Resin