Albumin and bilirubin

Most opioids have low protein binding, so alterations in albumin and bilirubin are unlikely to alter free drug levels. 

Metoclopramide, domperidone, ondansetron and granisetron are not highly protein bound, so they are unlikely to be affected by changes in albumin and bilirubin. 

Despite cirrhosis, this patient is maintaining good hepatocyte function (normal albumin and bilirubin, mildly raised INR) and the metabolic and excretory capacity of the liver should not be significantly reduced. The patient has portal hypertension, so blood flow to the liver will be impaired, which will reduce first-pass metabolism of highly extracted drugs (extraction ratio >0.7). This will result in greater bioavailability... 

In contrast, in a prospective study of 87 postmenopausal women who took a dry extract of black cohosh 40 mg/day for 12 months total hepatic blood fiow, assessed by color Doppler ultrasound, was unaffected as were prothrombin time and concentration, serum albumin and bilirubin concentrations, and gamma-glutamyltransferase, alkaline phosphatase, and aminotransferase activities [33 ]. However, these results do not rule out an incidence of hepatotoxicity of up to 3.4%. 

In HCC altered liver function is often determined by the underlying disease, such as hepatitis and cirrhosis, which may also settle the overall life quality and expectancy. The most reliable laboratory parameters for liver function are prothrombin time, albumin, and bilirubin, where normal values indicate a significantly better outcome in any therapy (Tateishi et al. 2005 Varela et al. 2003). Tumor markers such as alpha-fetoprotein - significantly elevated in HCC in about two-thirds of cases - and C-reactive protein maybe used mainly for follow-up to assess the response (Hashimoto et al. 2005). 

In the liver, the bilirubin is removed from albumin and taken up at the sinusoidal surface of the hepato-cytes by a carrier-mediated saturable system. This facilitated transport system has a very large capacity, so that even under pathologic conditions the system does not appear to be rate-limiting in the metabolism of bilirubin. 

Albumin, which is not glycosylated, is the major protein and is the principal determinant of intravascular osmotic pressure it also binds many Hgands, such as drugs and bilirubin. 

Liver function, including AST, ALT, alkaline phosphatase, lactate dehydrogenase (LDH), total and conjugated bilirubin a comprehensive metabolic panel can be ordered (i.e., sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, AST, ALT, alkaline phosphatase, albumin, and total bilirubin), but phosphorus, magnesium, and fractionated... 

Mir MM, Fazili KM, Abul Qasim M. Chemical modification of buried lysine residues of bovine serum albumin and its influence on protein conformation and bilirubin binding. Biochim. Biophys. Acta 1992 1119 261-267. 

Routine liver assessment tests include alkaline phosphatase, bilirubin, aspartate transaminase, alanine transaminase, and y-glutamyl transpeptidase (GGT). Additional markers of hepatic synthetic activity include albumin and prothrombin time. The substances are typically elevated in chronic inflammatory liver diseases such as hepatitis C, but may be normal in others with resolved infectious processes. 

Draw a baseline set of blood samples for liver enzymes, bilirubin, albumin, and transferrin before beginning the drug... 

Albumin has a molecular mass of approximately 66 000 and is synthesized at a rate of about 12 g, equal to 3% of total body albumin, per day to replace that which is degraded or lost. Impaired albumin synthesis and therefore a low plasma albumin concentration, is a hallmark of chronic liver disease. Several functions can be ascribed to albumin including osmotic (oncotic) pressure regulation of the plasma and a non-specific transport protein for ligands such as calcium, fatty acids, drugs and bilirubin. 

Fluorescein (excitation and emission maxima of 492 nm and 520 nm, respectively) has also been utilized in fluorescence assays. Although its excitation maximum is higher than that of umbelliferone, it suffers from a problem similar to that of umbelliferone in that albumin-bound bilirubin has excitation and emission maxima of 460 nm and 515 nm, respectively. In addition, commercial preparations have been reported to contain two isomers, which may cause heterogeneity during conjugate preparation. 

Serum albumin is the most abundant protein in blood plasma. Its primary function is to control the colloidal osmotic pressure in blood, but is also important for its buffering capacity and for its ability to transport fatty acids and bilirubin, as well as xenobiotic molecules. The physiological implications of its esterase-like activity are unknown (see Sect. 3.7.5). 

Population PK screening in Phase II and Phase III is useful in assessing the impact of altered hepatic function (as a covariate) in PKs, if those patients are not excluded from Phase II and III trials, and if there is sufficient PK information collected about the patients to characterize them reasonably well. If a population PK approach is used, patients in Phase II and III studies are assessed for encephalopathy, ascites, serum bilirubin, serum albumin, and prothrombin time (which are components of the Child-Pugh score) or a similar group of measures of hepatic function. The population PK study, then, would include the following features ... 

With severe hemolysis, more bihrubin is released into the blood than can be transported on albumin and conjugated in the liver. Unconjugated and total bilirubin increase and may produce jaundice and kernicterus. Examples include ... 

With albumin-solubilized bilirubin, pH optima of microsomal bilirubin UDP-glucuronyltransferase were 7.4-8.0 for rat (H2, HIO, SIO) and 7.4 for guinea pig (M13) and rabbit (T8). Above pH 8 the enzyme activity decreased abruptly (HIO). In absence of carrier protein, optima were at pH 8 and 8.2 with preparations from liver of guinea pig (P3) and rat (W12), respectively. The activity-pH curve with optimum at pH 8.2 (W12) showed pronounced skewing, with a steady and rather rapid increase of enzyme activity from pH 7.4 to 8.2. One may wonder whether such measurements were influenced by the rapid increase of solubility of the acceptor substrate occurring over the same pH range (B25). 

With UDP-glucuronic acid as the variable substrate and bilirubin at constant concentration, Michaelis-Menten kinetics were obeyed (A2, H2, HIO, P5, V2, W12). Rat liver microsomal preparations treated in different ways yielded apparent Km for UDP-glucuronic acid of 0.37-0.70 mM (A2, H2, HIO, V2), with albumin-bound bilirubin as the aglycon a higher value (1.66 mAf) was found in a carrier-free system (W12). These values probably do not represent Km for UDP-glucuronic acid at saturation with bilirubin (P5, V6). Under certain conditions of activation, cell extracts from livers of newborn and adult rats, wdicn tested with o-amino-... 

YS Fung, DX Sun, CY Yeung. Capillary electrophoresis for determination of free and albumin-bound bilirubin and the investigation of drug interaction with bilirubin-bound albumin. Electrophoresis 21 403-410, 2000. 

Hepatic Effects. Carbon tetrachloride has been known for many years to be a powerful hepatotoxic agent in humans and in animals. The principal clinical signs of liver injury in humans who inhale carbon tetrachloride are a swollen and tender liver, elevated levels of hepatic enzyme (aspartate aminotransferase) in the serum, elevated serum bilirubin levels and the appearance of jaundice, and decreased serum levels of proteins such as albumin and fibrinogen (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). In cases of acute lethal exposures, autopsy generally reveals marked liver necrosis with pronounced steatosis (Jennings 1955 Markham 1967 Smetana 1939), and repeated or chronic exposures leads in some cases to fibrosis or cirrhosis (McDermott and Hardy 1963). 

Detection of liver injury has commonly been associated with alternations in serum levels of certain hepatic enzymes and proteins. Elevation in bilirubin levels following exposure (Barnes and Jones 1967) has been detected in humans, as have decreased serum levels of secreted liver proteins (e.g., albumin and fibrinogen) (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). Elevations in serum levels of enzymes (e.g., ALT, AST, LDFI, OCT) have been reported following acute- and intermediate-duration exposures to carbon tetrachloride in animals (Bruckner et al. 1986 FI ayes et al. 1986 Sakata et al. 1987). 

Albumin is a major transport facilitator of hydrophobic compounds which would otherwise disrupt cellular membranes. These compounds include free fatty acids and bilirubin as well as hormones such as cortisol, aldosterone, and thyroxine when these materials have exceeded the capacity of proteins normally associated with them. Albumin also binds ions, including toxic heavy metals and metals such as copper and zinc which are essential for normal physiological functioning but may be toxic in quantities in excess of their binding capacity for their carrier proteins. Binding of protons is the basis for the buffering capacity of albumin. 

Albumin is the most abundant protein in human and other animal plasma. It is estimated that up to 40% of the total albumin in humans is in circulation transporting essential nutrients, especially those that are sparingly soluble in aqueous-based plasma. For example, the fatty acids, which are important fuel molecules for the peripheral tissue, are distributed by albumin. In addition, albumin is the plasma transport protein for other substances including bilirubin, thyroxine, and steroid hormones. Also, many drugs including aspirin, sulfanilamides, clofibrate, and digitalis bind to albumin and are most likely carried to their sites of action by the protein. 

It is noteworthy that the quantum yield of the blue emitting chromophore in phytochrome, associated with human serum albumin [105], which corresponds to an increase of more than 20 times over the solution d>f values of the latter compounds. The similarity of the values suggests that the radiationless decay processes of the bilirubin-type chromophore are less efficient owing to interaction with the phytochrome apoprotein. 

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