Hepatitis plasma proteins

Cirrhosis and other Uver diseases may result in the formation of excessive amounts of fluid in the abdomen ascites). The primary causes of ascites are usually elevation of pressure in the portal vein and a decreased amount of hepatic plasma protein production. Both factors tend to reduce the ability of the vascular compartment to retain fluid. The resultant ascites may contribute to decreased appetite and respiratory difficulties, among other symptoms. When these symptoms are present, careful reduction in the fluid volume through the use of diuretics is desirable. 

Bowman, B.H. (1993) Hepatic Plasma Proteins Mechanisms of Function and Regulation. Academic Press, San Diego, New York. 

EoUowing po administration moricizine is completely absorbed from the GI tract. The dmg undergoes considerable first-pass hepatic metabolism so that only 30—40% of the dose is bioavailable. Moricizine is extensively (95%) bound to plasma protein, mainly albumin and a -acid glycoprotein. The time to peak plasma concentrations is 0.42—3.90 h. Therapeutic concentrations are 0.06—3.00 ]l/niL. Using radiolabeled moricizine, more than 30 metabolites have been noted but only 12 have been identified. Eight appear in urine. The sulfoxide metabolite is equipotent to the parent compound as an antiarrhythmic. Elimination half-life is 2—6 h for the unchanged dmg and known metabolites, and 84 h for total radioactivity of the labeled dmg (1,2). 

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

Acebutolol is well absorbed from the GI tract. It undergoes extensive hepatic first-pass metabohsm. BioavailabiUty of the parent compound is about 40%. The principal metaboflte, A/-acetylacebutolol, has antiarrhythmic activity and appears to be more cardioselective. Binding to plasma proteins is only 26%. Peak plasma concentrations of acebutolol are achieved in 2.5 h, 3.5 h for A/-acetylacebutolol. The elimination half-Hves of acebutolol and its metabohte are 3—4 and 8—13 h, respectively. The compounds are excreted by the kidneys (30—40%) and by the Hver into the bile (50—60%). About 40% of the amount excreted in the urine is unchanged acebutolol, the rest as metabofltes (32). 

After po dosing, verapamil s absorption is rapid and almost complete (>90%). There is extensive first-pass hepatic metabolism and only 10—35% of the po dose is bioavahable. About 90% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 1—2 h, although effects on AV nodal conduction may be apparent in 30 min (1—2 min after iv adrninistration). Therapeutic plasma concentrations are 0.125—0.400 p.g/mL. Verapamil is metabolized in the liver and 12 metabolites have been identified. The principal metabolite, norverapamil, has about 20% of the antiarrhythmic activity of verapamil (3). The plasma half-life after iv infusion is 2—5 h whereas after repeated po doses it is 4.5—12 h. In patients with liver disease the elimination half-life may be increased to 13 h. Approximately 50% of a po dose is excreted as metabolites in the urine in 24 h and 70% within five days. About 16% is excreted in the feces and about 3—4% is excreted as unchanged dmg (1,2). 

Plasma protein fractions are used to treat hypovolemic (low blood volume) shock that occurs as the result of bums, trauma, surgery, and infections, or in conditions where shock is not currently present but likely to occur. Plasma protein fractions are also used to treat hypoproteinemia (a deficiency of protein in the blood), as might be seen in patients with nephrotic syndrome and hepatic cirrhosis, as well as other diseases or disorders. As with human pooled plasma, blood type and crossmatch is not needed when plasma protein fractions are given. 

Plasma proteins are contraindicated in those with a history of allergic reactions to albumin, severe anemia, or cardiac failure in the presence of normal or increased intravascular volume and in patients on cardiopulmonary bypass. Plasma protein fractions are used cautiously in patients who are in shock or dehydrated and in those with congestive cardiac failure or hepatic or renal failure. These solutions are Pregnancy Category C drugp and are used cautiously during pregnancy and lactation. 

Albumin (69 kDa) is the major protein of human plasma (3.4-4.7 g/dL) and makes up approximately 60% of the total plasma protein. About 40% of albumin is present in the plasma, and the other 60% is present in the extracellular space. The liver produces about 12 g of albumin per day, representing about 25% of total hepatic protein synthesis and half its secreted protein. Albumin is initially synthesized as a preproprotein. Its signal peptide is removed as it passes into the cisternae of the rough endoplasmic reticulum, and a hexapeptide at the resulting amino terminal is subsequently cleaved off farther along the secretory pathway. The synthesis of albumin is depressed in a variety of diseases, particularly those of the liver. The plasma of patients with liver disease often shows a decrease in the ratio of albumin to globulins (decreased albumin-globuhn ratio). The synthesis of albumin decreases rela-... 

As described above, it will be normal to assume that the dose interval is 24 hours, i.e., once-a-day dosing. Absorption can be estimated with good confidence from absorption in the rat (see Section 6.1). Clearance is the sum of the predicted hepatic, renal, biliary and extrahepatic clearance. Hepatic clearance can be derived from in vitro studies with the appropriate human system, using either microsomes or hepatocytes. We prefer to use an approach based on that described by Houston and Carlile [83], Renal clearance can be predicted allometrically (see section 6.8.1). The other two potential methods of clearance are difficult to predict. To minimize the risks, animal studies can be used to select compounds that show little or no potential for clearance by these routes. As volume can be predicted from that measured in the dog, after correction for human and dog plasma protein binding (see Section 6.2), it is possible to make predictions for all of the important parameters necessary. 

T or si Free fraction of highly plasma protein-bound drugs si Clearance and T t1/2 for some oxidatively metabolized drugs si Clearance and T t1/2 for drugs with high hepatic extraction ratios si Clearance and T t 2 for renally eliminated drugs and active metabolites... 

Pharmacokinetics When administered intravenously, ICG rapidly binds to plasma proteins and is exclusively cleared by the liver, and subsequently secreted into the bile [8]. This forms the basis of the use of ICG for monitoring hepatic blood flow and function. Two pharmacokinetics models, a monoexponential decay, which describes the initial rapid clearance of ICG with a half-life of about 3 minutes (Eq. (1)) and a bi-exponential model, which incorporates the secondary phase clearance with a longer half-life (Eq. (2)), describe total clearance of ICG from plasma [ 132]. For real-time measurements by continuous organ function monitoring, the mono-exponential decay is preferred. 

Plasma protein-bound drugs that are substrates for transport carriers can be cleared from blood at great velocity, e.g., p-aminohippurate by the renal tubule and sulfobromophthalein by the liver. Clearance rates of these substances can be used to determine renal or hepatic blood flow. 

Quinidine is rapidly absorbed from the Gl tract. Maximum effects of quinidine gluconate occur 30 to 90 minutes after IM administration onset is more rapid after IV administration. Activity persists for at least 6 to 8 hours. The average therapeutic serum levels are reported to be 2 to 7 mcg/mL. Toxic reactions may occur at levels from 5 to 8 mcg/mL or more. Quinidine is 80% to 90% bound to plasma proteins the unbound fraction may be significantly increased in patients with hepatic insufficiency. 

Buprenorphine is metabolized by the liver mediated by cytochrome P450 3A4, and its clearance is related to hepatic blood flow. Plasma protein binding is about 96%. The mean elimination half-life from plasma is 37 hours. 

Pharmacokinetics The elimination half-lives of these drugs range from 4 to 8 hours. Elimination is primarily via hepatic metabolism. Plasma concentrations of alosetron are 30% to 50% lower and less variable in men compared with women given the same dose. Plasma protein binding is 82% for alosetron, 65% for granisetron and 70% to 76% for ondansetron. The terminal elimination half-life of alosetron is approximately 1.5 hours. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Distribution - The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses. Varying degrees of hepatic and renal insufficiency do not affect the protein... 

Absorption/Distribution - Pyrazinamide is well absorbed from the Gl tract and attains peak plasma concentrations within 2 hours. It is widely distributed in body tissues and fluids including the liver, lungs, and cerebrospinal fluid. Pyrizinamide is approximately 10% bound to plasma proteins. Metabolism/Excretion - The half-life is 9 to 10 hours it may be prolonged in patients with impaired renal or hepatic function. 

What makes prediction of drug elimination complex are the multiple possible pathways involved which explain why there is no simple in vitro clearance assay which predicts in vivo clearance. Because oxidative metabolism plays a major role in drug elimination, microsomal clearance assays are often used as a first line screen with the assumption that if clearance is high in this in vitro assay it is likely to be high in vivo. This assumption is often, but not always true because, for example, plasma protein binding can limit the rate of in vivo metabolism. However, compounds which have a low clearance in hepatic microsomes can be cleared in vivo via other mechanisms (phase II metabolism, plasmatic errzymes). Occasionally, elimination is limited by hepatic blood flow, and other processes like biliary excretion are then involved. The conclusion is that the value of in vitro assays needs to be established for each chemical series before it can be used for compound optimization. 

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