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However buy discount cleocin on-line acne en la espalda, as dis- isoform involved in human drug metabolism generic cleocin 150mg with mastercard acne reviews, both in cussed later buy cleocin with a visa skin care qvc, there is still a great deal of substrate speci- terms of the amount of enzyme in the liver and the vari- ficity within a given enzyme family. It is becoming increasingly clear that dif- ferent enzyme expression patterns, and thus different drug metabolism capabilities, are observed throughout This isoform may account for more than 50% of all the various stages of life. In fact, it is believed that drugs as substrates, its relative abundance in the liver is two drugs (substrates) can occupy the active site simul- quite low. Any change Involved in Human Drug in the metabolism of these two drugs, either increased Metabolism or decreased, can have profound adverse effects. Enzyme Inhibition hibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme Enzyme inhibition is the most frequently observed re- and prevents any further metabolism by the enzyme. The most the enzyme molecule and thus can be overcome only by common type of inhibition is simple competitive inhibi- the proteolytic degradation of that particular enzyme tion, wherein two drugs are vying for the same active molecule and subsequent synthesis of new enzyme pro- site and the drug with the highest affinity for the site tein. Whereas decreased to such a degree that the patient is exposed one frequently associates enzyme inhibition with an in- to 17 times as much of parent triazolam as when keto- crease in potential for toxicity, enzyme induction is most conazole is not present. Both time required for synthesis of Depending on the isoform, these enzymes have varying new enzyme protein (transcription and translation) and reactivity toward a number of pharmacologically active the half-life of the inducing drug affect the time course compounds, such as opioids, androgens, estrogens, of induction. Little taching (conjugating) a more polar molecule to the overlap in substrate specificities of the two isoforms original drug molecule to increase water solubility, appears to exist. A representative tabolism of a number of drugs, neurotransmitters, reaction of this type is shown in Figure 4. Like the afore- etary supplement for the treatment of various condi- mentioned enzymes, sulfate conjugation typically ren- tions. Likelihood of adverse topurine so that the dose may be adjusted downward if events, such as the dyskinesias associated with certain they are found to be deficient in this enzyme. Though most drug metabolism enzymes reside in the Recently, variant alleles (and thus polymorphisms) liver, other organs may also play an important role. As leaves its site of action, it may remain in the body for a early as the late 1950s it was recognized that individuals considerable period, especially if it is strongly bound to might differ in whether they could acetylate certain tissue components. In this case, activity and drug elimination are to be seen as related the individuals studied appeared to segregate into two but separate phenomena. Excretion, along with metabolism and tissue redis- It was later discovered that this polymorphism ex- tribution, is important in determining both the duration isted in the N-acetyltransferase-2 gene and thus the of drug action and the rate of drug elimination. More important, it has become clear Excretion is a process whereby drugs are transferred that slow acetylators (about 50% of the caucasian popu- from the internal to the external environment, and the lation) are more prone to adverse effects following ad- principal organs involved in this activity are the kid- ministration of certain drugs than fast acetylators. As the ultrafiltrate is formed, Glomerular Filtration any drug that is free in the plasma water, that is, not The ultrastructure of the glomerular capillary wall is bound to plasma proteins or the formed elements in the such that it permits a high degree of fluid filtration while blood (e. This selective filtration is im- All unbound drugs will be filtered as long as their mo- portant in that it prevents the filtration of plasma pro- lecular size, charge, and shape are not excessively large. The greater restriction to filtration of back-diffusion occurs primarily in the distal tubules and charged molecules, particularly anions, is probably collecting ducts, where most of the urine acidification due to an electrostatic interaction between the filtered takes place. Since it is the un-ionized form of the drug molecule and the fixed negative charges within the that diffuses from the tubular fluid across the tubular glomerular capillary wall. These highly anionic struc- cells into the blood, it follows that acidification in- tural components of the wall contribute to an electro- creases reabsorption (or decreases elimination) of weak static barrier and are most likely in the endothelial or acids, such as salicylates, and decreases reabsorption (or glomerular basement membrane regions. Differences in the not have sufficient lipid solubility, urinary pH changes three-dimensional shape of macromolecules result in a will have little influence on urinary drug excretion. For example, one can enhance the cient retention of proteins within the circulation is at- elimination of a barbiturate (a weak acid) by adminis- tributed to a combination of factors, including their tering bicarbonate to the patient. This procedure alka- globular structure, their large molecular size, and the linizes the urine and thus promotes the excretion of the magnitude of their negative charge. For through the use of an acidifying salt, such as ammonium instance, inflammation of the glomerular capillaries chloride. Anything that alters drug–protein A number of drugs can serve as substrates for the two binding, however, will change the drug filtration rate. The usual range of half-lives seen for most drugs that These transport systems, which actively transfer drugs are cleared solely by glomerular filtration is 1 to 4 hours. One drug substrate can Also, since water constitutes a larger percentage of compete for transport with a simultaneously adminis- the total body weight of the newborn than of individu- tered or endogenous similarly charged compound; this als in other age groups, the apparent volume of distri- competition will decrease the overall rate of excretion bution of water-soluble drugs is greater in neonates. The secretory capacity of both the or- This results in a lower concentration of drug in the ganic anion and organic cation secretory systems can be blood coming to the kidneys per unit of time and hence saturated at high drug concentrations. In general, the movement of drugs is favored from the tubular lumen to blood, partly because of the reabsorption of water that occurs throughout most portions of the nephron, which results in an increased concentration of drug in the luminal Active transport fluid.

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These drugs can cause dizziness and asthenia order 150mg cleocin with amex acne oral medication, even capacity by diminishing unstable detrusor contractions discount 150 mg cleocin acne bumps under skin. Nasal Both drugs may cause dry mouth and blurred vision cheap cleocin online american express acne 8th ave, and stuffiness can be a problem – especially in patients who may precipitate glaucoma. Flavoxate has less marked side- which selectively blocks the a subclass7 of adrenoceptors 1A effects but is also less effective. Propiverine, tolterodine and and is therefore less likely to affect blood pressure, pro- trospium are also antimuscarinic drugs used for urinary fre- vided the single 400-microgram daily dose of tamsulosin quency, urgency and incontinence. Imipramine, amitriptyline and not affect serum testosterone, or most non-prostatic nortriptyline are effective, especially for nocturnal but also responses to testosterone. Their parasympathetic blocking about 20% and increases urinary flow rates by a similar (antimuscarinic) action is probably in part responsible, but degree. These changes translate into modest clinical bene- imipramine may also benefit by altering the patient’s sleep fits, which are generally inferior to those of an a 1 profile. Oestrogens, either applied locally to the vagina or Finasteride (t½ 6 h) is taken as a single 5-mg tablet each taken by mouth, may benefit urinary incontinence due to day. The improvement in urine flow appears over 6 months atrophy of the urethral epithelium in post-menopausal (as the prostate shrinks in size), and in 5–10% of patients women. Although this may reflect a real reduction in risk of chol and distigmine, may be used to stimulate the detrusor prostatic cancer, in patients receiving finasteride it is safer when the bladder is hypotonic, e. Lower doses of finasteride have is preferred but, as its effect is not sustained, intermittent also been used successfully to halt the development catheterisation is also needed when the hypotonia is 8 of baldness. The prostate gland is a mixture of capsular 7 There are three cloned subtypes for the a1-adrenoceptor: a1A, a1B and and stromal tissue, rich in a1 adrenoceptors, and glandular a. Thea isthepredominantsubtypeinthebladderbaseandprostatic 1D 1A tissue under the influence of androgens. Both these, the a urethra, whereas contraction of vascular smooth muscle is largely receptors and androgens, are targets for drug therapy. Hence, a1A selectivity would confer, at cause the bladder itself has few a receptors, it is possible least in principle, ‘prostatic’ selectivity. But selectivity determined in vitro against cloned a1 receptors only poorly predicts in vivo to use selective a1-blockade without affecting bladder ‘uroselectivity’, which also diminishes as dose is increased (compare contraction. They cause sig- increased in balding scalps (Tartagni M, Schonauer M, Cicinelli E et al 1 2004 Intermittent low-dose finasteride is as effective as daily nificant increases (compared to placebo) in objective mea- administration for the treatment of hirsute women. Adverse effects areshortlived,doserelated,andcomprise headache, flushing, nasal congestion and dyspepsia. Sildenafil is contraindicated in patients who evidence is not conclusive, drug therapy is thought to under- are taking organic nitrates, for their metabolism is blocked lie 25% of cases, reputedly from antidepressants (selective and severe and acute hypotension result. This latter could be viewed as a mixed compressed between the engorged sinusoids and the sur- blessing in erectile dysfunction, but is important for the use rounding and firm tunica albuginea, causing the near-total of this drug class in pulmonary hypertension. Theprincipalneu- Alprostadil is a stable form of prostaglandin E1, a power- rotransmitterisnitricoxide,whichactsbyraisingintracellular ful vasodilator (see p. Its dose (5–20 micrograms) is titrated initially in the doctor’s emergence as an agent for erectile dysfunction is an exam- surgery, aiming for an erection lasting for not more than ple of serendipity in drug development. The drug reminiscent of the disturbed colour perception caused by digoxin (in should be taken 1 h before intercourse in an initial dose overdose), except here patients report yellowed vision (xanthopsia). It is effective (up to 80%) for can cause priapism requiring aspiration of the corpora psychogenic and neurogenic erectile dysfunction by intra- cavernosa and injection of an a-adrenoceptor agonist, cavernosal self-injection shortly before intercourse (efficacy e. Summary • The actions of drugs on the kidney are of an importance antihypertensive efficacy than loop diuretics. It is among the functions of drugs to help • Potassium retention with hyperkalaemia can occur with reduce losses of desirable substances and increase losses of potassium-sparing diuretics, which block sodium transport undesired substances. The symptoms of benign prostatic hyperplasia are • Loop diuretics, acting on the ascending loop of Henle, are partially relieved either by a1-adrenoceptor blockade or by the most effective, and are used mainly to treat the oedema inhibiting synthesis of dihydrotestosterone in the prostate. Cough is useful when it effectively expels secretions or for- Central nervous system eign objects from the respiratory tract, i.

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However discount cleocin 150mg overnight delivery acne zits, the develop- called glucocorticoid response elements in the pro- ment of resistance may limit the effectiveness of steroid moter–enhancer regions of responsive genes (Fig purchase 150 mg cleocin acne rosacea. Because their side effects are thought to be a Prompt intensive treatment with corticosteroids may be consequence of gene induction buy on line cleocin acne regimen, glucocorticoids that can lifesaving when an excessive inflammatory reaction has repress inflammatory genes without inducing gene tran- resulted in septic shock. This protective role of steroids may cellular responsiveness are directly proportional to the be due to a direct effect on vascular smooth muscle. A decrease in gluco- combination of glucocorticoids and dopamine therapy corticoid receptor number (down-regulation) produced preserves renal blood flow during shock. Down- regulation of glucocorticoid receptors also is a potential Congenital Adrenal Hyperplasia mechanism for terminating glucocorticoid-dependent Congenital enzymatic defects in the adrenal biosyn- responses and for curtailing excessive cell stimulation thetic pathways lead to diminished cortisol and aldo- when circulating levels of steroids are high. In these conditions, tiveness of glucocorticoids will also be compromised by corticotrophin secretion is increased, and adrenal hy- the concomitant administration of other drugs that en- perplasia occurs, accompanied by enhanced secretion of hance the clearance of glucocorticoids (ephedrine, steroid intermediates, especially adrenal androgens. However, in other tissues gluco- Membrane phospholipids corticoids may exert their actions through mineralocor- ticoid receptors. Several actions of glucocorticoids that are too rapid to be explained by actions on transcription are mediated by effects on membrane receptors. Because glucocorticoids regulate gene expression and Glucocorticoids (induce lipocortin) protein synthesis, there is generally a lag of several hours before their effects are manifest. This may account for the fact that side effects elicited by Arachidonic acid steroids can be minimized by alternate-day therapy. Steroids may exert a primary effect at the inflammatory site by inducing the synthesis of a Glucocorticoids group of proteins called lipocortins. Although may also contribute to the antiinflammatory effects of the short cosyntropin test is recognized as a valid glucocorticoids. The resulting reduction in the negative feed- residues, the first 24 of which are essential for its biolog- back of cortisol on the hypothalamus and pituitary ical activity. The remainder of the amino acids are also causes an increase in corticotrophin release and in the clinically important, since they may be involved in stim- secretion of precursor 11-deoxysteroids. Metyrapone is used in the differential diagnosis of both adrenocortical insufficiency and Cushing’s syndrome Absorption, Metabolism, Excretion (hypercortisolism). The drug tests the functional com- Corticotropin is rapidly inactivated by gastrointestinal petence of the hypothalamic–pituitary axis when the proteolytic enzymes and therefore must be administered adrenals are able to respond to corticotrophin; that is, parenterally. Moreover, if pituitary corticotrophin is suppressed by an autonomously secret- The rationale for using corticotropin instead of phar- ing adrenal carcinoma, there will be no increase in re- macological concentrations of glucocorticoids stems sponse to metyrapone. On the other hand, if pituitary from the fact that corticotropin provides enhanced corticotrophin secretion is maintained, as occurs in adre- amounts of all endogenously secreted adrenocortical nal hyperplasia, the inhibition of corticoid synthesis pro- hormones, including androgens. However, obvious dis- duced by metyrapone will stimulate corticotrophin secre- advantages are associated with the use of this polypep- tion and the release of metabolites of precursor urinary tide: (1) It must be given daily parenterally. Corticotropin differential diagnosis of Cushing’s syndrome because of is used as a diagnostic tool for the identification of pri- the ability to measure plasma corticotrophin directly. However, the compensa- Adverse Effects tory rise in corticotrophin levels in response to falling Aside from hypersensitivity and allergic reactions, cor- cortisol levels tends to maintain adrenal activity. This re- ticotropin administration has been associated with elec- quires that glucocorticoids be administered concomi- trolyte disturbances and masculinization in women. Although metyrapone interferes with 11 - and 18- hydroxylation reactions and thereby inhibits aldos- Cosyntropin terone synthesis, it may not cause mineralocorticoid de- Cosyntropin (Cortrosyn) is a polypeptide that consists ficiency because of the compensatory increased produc- solely of the first 24 amino acids of corticotropin. Being a lipid-soluble substance, mitotane remains Side effects associated with the use of metyrapone in- stored in body tissues for extended periods. This may clude gastrointestinal distress, dizziness, headache, seda- account for the marked patient-to-patient variability in tion, and allergic rash. When administered primary adrenal carcinoma when surgery or radiation to pregnant women during the second or third tri- therapy is not feasible (see Chapter 56). Its effective- mesters, the drug may impair steroid biosynthesis in the ness in curtailing adrenal activity is due to an action on fetus. Because metyrapone is relatively nontoxic, it is adrenocortical mitochondria to impair cytochrome used in combination therapy with the more toxic amino- P450 steps in steroid biosynthesis. It is Aminoglutethimide (Cytadren) is a competitive in- advised to measure serum mitotane levels and urinary hibitor of desmolase, the enzyme that catalyzes the con- free cortisol excretion to ensure adequate therapeutic version of cholesterol to pregnenolone; it also inhibits concentrations. This drug also reduces estrogen terol by inhibiting cytochrome P450–mediated reac- production by inhibiting the aromatase enzyme com- tions and therefore contributes to the cardiovascular plex in peripheral (skin, muscle, fat) and steroid target events that are a significant cause of mortality in un- tissues. Such a medical adrenalectomy is an efficacious Mitotane, being closely related to the organochlo- treatment for metastatic breast and prostate cancer, rine insecticides, shares its inductive effects on the liver since it diminishes the levels of circulating sex hor- microsomal drug-metabolizing enzyme system, and its mones. Glucocorticoids are administered concomitantly use may therefore alter the requirement for concomi- to suppress enhanced corticotrophin release.

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The therapeutic range should be considered as an initial guideline for drug concentrations in a specific patient; drug dose and steady-state concentrations should then be titrated and individualized based on therapeutic response generic cleocin 150 mg line acne face chart. For example generic cleocin 150 mg online acne on back, the therapeutic range for theophylline is generally accepted as 10–20 μg/mL for the treatment of asthma with con- centrations of 8–12 μg/mL considered as a reasonable starting point best buy cleocin skin care talk. The definition of clearance is the volume of serum or blood completely cleared of the drug per unit time. The liver is most often the organ responsible for drug metabolism while in most cases the kidney is responsible for drug elimination. The gastrointestinal wall, lung, and kidney can also metabolize some drugs, and some medications are eliminated unchanged in the bile. In either case, the resulting metabolite is more water soluble than the parent drug, and is more likely to be eliminated in the urine. This fam- ily of enzymes is very important to understand because specific enzymes are responsible for the metabolism of each drug entity. Once it is known that a patient is deficient in one of the enzymes, usually because the clearance of a known drug substrate is very low resulting in high steady-state serum concentrations for a low to moderate dose, it can be inferred that all drugs metabolized by that enzyme will have a low clearance, and doses of other drugs that are substrates of the enzyme may be empirically reduced. If a meta- bolic drug interaction occurs between one medication and another known to be a sub- strate for a specific enzyme, it can be assumed that a drug interaction will occur between that drug and other substrates of the same enzyme. The enzymes are classified using a series of numbers and letters, and indicate how closely related the enzymes are to each other using amino acid sequencing. Once drug molecules have entered the urine by either of these processes, it is possible that the molecules may reenter the blood via a process known as tubular reab- sorption. John’s Wart Cetirizine Cyclosporine Rifampin Cyclosporine Diltiazem Daunorubicin Erythromycin Desloratadine Grapefruit juice Digoxin Indinavir Diltiazem Itraconazole Doxorubicin Ketoconazole Erythromycin Nicardipine Etoposide Nelfinavir Fexofenadine Propafenone Indinavir Quinidine Loperamide Ritonavir Nelfinavir Saquinavir Ondansetron Tacrolimus Paclitaxel Tamoxifen Quinidine Testosterone Rifampin Verapamil Ritonavir Saquinavir Tacrolimus Verapamil Vinblastine Vincristine facilitates the transfer of drug across the kidney tubule. The majority of drug tubular secretion takes place in the proximal tubule of the nephron while tubular reabsorption usually takes place in the distal tubule of the nephron. The clearance for an organ, such as the liver or kidney, that metabolizes or eliminates drugs is determined by the blood flow to the organ and the ability of the organ to metabo- lize or eliminate the drug. However, the extraction ratio is oftentimes determined during the drug development process, and knowledge of this parameter can be extremely useful in determining how the pharmacokinetics of a drug will change during a drug interaction or if a patient develops hepatic, renal, or cardiac failure. The drug clearance for an organ is equal to the product of the blood flow to the organ and the extraction ratio of the drug. When drug molecules (D) enter an organ (blood flows from left to right) that clears the drug, they may be bound to plasma proteins (trapezoid shapes) or exist in the unbound state. The unbound or “free” drug molecules are in equilibrium with the bound drug in the blood and unbound drug in the tissue. Drug molecules that have entered hepatic tissue may encounter an enzyme (E) that metabolizes the drug. When this occurs the drug is chemically converted to a metabolite (M) which can diffuse back into the blood and leave the liver along with drug mole- cules that were not metabolized. The total clearance for a drug is the sum of the individual clearances for each organ that extracts the medication. For example, the total clearance (Cl) for a drug that is metabolized by the liver and eliminated by the kidney is the sum of hepatic and renal clearance for the agent: Cl = ClH + ClR. The intrinsic clearance (Cl′int) is the inherent abil- ity of the enzyme to metabolize the drug and is the quotient of the Michaelis-Menten con- stants Vmax (maximum rate of drug metabolism) and Km (drug concentration at which the metabolic rate equals Vmax/2; Cl′int = Vmax/Km) for the unbound drug. The unbound frac- tion of drug in the blood or serum (fB) is the unbound drug concentration divided by the total (bound + unbound) drug concentration. In this case, drug interactions that displace drug molecules bound to proteins will increase the fraction of unbound drug in the blood (↑fB); more unbound drug molecules will be able to leave the vascular system (drug-protein complexes are far too big to exit the vascular system) and enter hepatocytes where the additional unbound drug will be metabolized and hepatic drug clearance will increase. Additionally, drug interactions that inhibit or induce the cytochrome P-450 enzyme system (decreasing or increasing Cl′int, respectively) will change the hepatic clearance of the medication accordingly. The hepatic clearance of drugs with low extraction ratios does not change much when liver blood flow decreases secondary to liver or cardiac disease. The rate limiting step for drug metabolism in this case is how much drug can be delivered to the liver because the capacity to metabolize drug is very large. In this case, hepatic clearance is very sensitive to changes in liver blood flow due to congestive heart failure or liver disease. However, the hepatic clearance of drugs with high extraction ratios does not change much when protein binding displacement or enzyme induction or inhibition occurs due to drug interactions.

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For infusion discount cleocin 150mg free shipping acne medication accutane, the frozen cryoprecipitate unit is thawed and dissolved in a small volume of sterile citrate-saline solution and pooled with other units cheap 150 mg cleocin otc skin care khobar. Rh-negative women with potential for childbearing should receive only Rh-negative cryoprecipitate because of possible contamination of the product with Rh-positive blood cells generic 150mg cleocin overnight delivery acne jawline. For hemophilia A or B with inhibitors and bleeding, the dosage is 90 mg/kg every 2 hours until hemostasis is achieved, and then continued at 3–6 hour intervals until stable. This study found an increase in arterial, but not venous, thrombotic events, particularly among elderly individuals. When the drug is administered intravenously, a 5 g loading dose should be infused over 30 minutes to avoid hypotension. Treatment success has also been reported in patients with postsurgical gastrointestinal bleeding and postprostatectomy bleeding and bladder hemorrhage secondary to radiation- and drug-induced cystitis. Adverse effects of the drug include intravascular thrombosis from inhibition of plasminogen activator, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness. The drug should not be used in patients with disseminated intravascular coagulation or genitourinary bleeding of the upper tract, eg, kidney and ureters, because of the potential for excessive clotting. It also inhibits the plasmin-streptokinase complex in patients who have received that thrombolytic agent. Aprotinin was shown to reduce bleeding—by as much as 50%—from many types of surgery, especially that involving extracorporeal circulation for open heart procedures and liver transplantation. However, clinical trials and internal data from the manufacturer suggested that use of the drug was associated with an increased risk of renal failure, heart attack, and stroke. A prospective trial was initiated in Canada but halted early because of concerns that use of the drug was associated with increased mortality. Fuster V et al: Guided antithrombotic therapy: Current status and future research direction: Report on a National Heart Lung and Blood Institute working group. Given that the thrombotic event occurred in the setting of oral contraceptive use, the patient should be counseled to use an alternative form of contraception. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. Remnant lipoproteins formed during the catabolism of chylomicrons that contain the B-48 protein (apo B-48) can also enter the artery wall, contributing to atherosclerosis. Cellular components in atherosclerotic plaques include foam cells, which are transformed macrophages, and smooth muscle cells filled with cholesteryl esters. These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. Whereas such lesions can slowly occlude coronary vessels, clinical symptoms are more frequently precipitated by rupture of unstable atheromatous plaques, leading to activation of platelets and formation of occlusive thrombi. Although treatment of hyperlipidemia can cause slow physical regression of plaques, the well-documented reduction in acute coronary events that follows vigorous lipid-lowering treatment is attributable chiefly to mitigation of the inflammatory activity of macrophages and is evident within 2–3 months after starting therapy. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Normal coronary arteries can dilate in response to ischemia, increasing delivery of oxygen to the myocardium. Reducing levels of atherogenic lipoproteins and inhibiting their oxidation restores endothelial function. Because atherogenesis is multifactorial, therapy should be directed toward all modifiable risk factors. Quantitative angiographic trials have demonstrated net regression of plaques during aggressive lipid- lowering therapy. Primary and secondary prevention trials have shown significant reduction in mortality from new coronary events and in all-cause mortality. Chylomicrons Chylomicrons are formed in the intestine and carry triglycerides of dietary origin, unesterified cholesterol, and cholesteryl esters. Unlike other cells, hepatocytes can eliminate cholesterol by secretion in bile and by conversion to bile acids. The (a) protein is highly homologous with plasminogen but is not activated by tissue plasminogen activator.

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