Hepatic extraction fraction

For those drugs dependent solely on hepatic elimination, total body clearance (CIt) equals hepatic clearance CIh). When the Ever is considered from a purely physiological perspective, the hepatic clearance is determined by the hepatic blood flow (Q) and the hepatic extraction fraction ( ). 

The hepatic extraction fraction of a drug reflects the affinity of a particular drug for hepatic microsomal enzymes E can be found experimentally or calculated by the following equation ... 

Enzymes of the hepatic microsomal system can be induced or inhibited. Enzyme induction and inhibition have greatest significance for drugs with low to moderate hepatic extraction fractions. 

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... 

The blood levels following oral and intravenous doses are very low in all animal species. This, most likely, is due to the marked affinity of the drug for various tissues and the rapid hepatic extraction of the absorbed fraction. The main route of excretion is the bile. Less than 5 % of the dose are recovered in the urine of intact animals after oral or intravenous administration. 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

Most drugs used in anaesthesia are metabolised in the liver by phase I reactions, mediated by cytochrome P-450 enzymes. These are susceptible to destruction by cirrhosis, so that the biotransformation of drugs, such as opioids (except morphine), benzodiazepines, barbiturates, and inhalational agents, may be markedly altered in severe liver disease. These enzymes are found in the centrilobular areas, which are more prone to hypoxia. In contrast, the enzymes responsible for phase II reactions, found predominantly in the peripheral areas, often function normally even in advanced disease. The disposition of benzodiazepines that are eliminated primarily by glucuronidation, e.g. lorazepam and oxazepam, are unaffected by chronic liver disease. For drugs with low hepatic extraction, advanced hepatocytic dysfunction decreases phase I and II biotransformation with a reduced clearance and prolongation of the elimination half-life. This is often partially offset by an increased free fraction due to decreased protein binding. 

However, the reductase inhibitors clearly induce an increase in high-affinity LDL receptors. This effect increases both the fractional catabolic rate of LDL and the liver s extraction of LDL precursors (VLDL remnants), thus reducing plasma LDL (Figure 35-2). Because of marked first-pass hepatic extraction, the major effect is on liver. Preferential activity in liver of some congeners appears to be attributable to tissue-specific differences in uptake. Limited reduction of LDL levels in patients who lack functional LDL receptors indicates that decreases in de novo cholesterologenesis also contribute to cholesterol reduction. Modest decreases in plasma triglycerides and small increases in HDL also occur. 

Similarly, five days of saquinavir administration (1200 mg, t.i.d.) inhibited the metabolic clearance of intravenous and oral midazolam (106). The oral bioavailability of midazolam increased from 41% to 90%. The hepatic availability fraction was estimated to have increased from 0.64 to 0.84 and the intestinal availability fraction increased from 0.64 to about 1.0. Thus, saquinavir treatment resulted in a near complete inhibition of first-pass intestinal extraction and a lesser inhibition of hepatic extraction of midazolam. 

It has been demonstrated that hepatic extraction ratio (ER) is also influenced by blood flow. A number of mathematical models have been proposed to explain this observation, but the simplest model, and the one that is easiest to apply to clinical practice, is the well stirred or venous equilibrium model (Equation 5.3). This model relates hepatic clearance to hepatic blood flow (Q), the fraction of drug concentration that is unbound in plasma (fu) and the intrinsic clearance of the unbound drug (Clyint) [1]. Intrinsic clearance represents the maximum clearance of drug in the absence of any restrictions caused by blood flow, binding or access to the metabolising enzymes. The model states that ... 

Answer The fraction of drug A excreted by the kidney (fe) = renal clearance/total clearance. Since 10% of the drug is excreted unchanged (fe = 0.1), it can be assumed that renal clearance = 0.1 x 80L/hour = 8 L/ hour. Assuming that Cltotal = Clrenal + Clhepatic, the hepatic clearance is 80 L/hour - 8 L/hour = 72 L/hour. The hepatic extraction ratio is given by the hepatic clearance divided by the hepatic blood flow, which, in this case, is EH = 72 L/hour/90 L/hour = 0.8. The maximal predicted oral bioavailability (F) is given by the product of the fractional hepatic clearance (fH), which is 1 minus the hepatic extraction ratio EH (1 — 0.8 = 0.2) and the fractional oral absorption (fD), assumed in this case to be unity (maximal case). Therefore, F = 0.2 x 1 = 0.2. 

A potentially important use of MTX diesters has been proposed to be in the treatment of tumours of the central nervous system [292]. Rosowsky et al. [309] examined the pharmacokinetics and metabolism of DBMTX in Rhesus monkeys, and demonstrated that when only free (i.c., not protein-bound) drug was considered, the CSF/plasma ratio for the diester, as well as for its major metabolite, MTX y-w-butyl ester, was indeed higher than the ratio for MTX. However, when account was taken of the fact that binding to plasma proteins was 90-95% for DBMTX as compared to only 50% for MTX, the ratios of total drug in the CSF and plasma compartments for the two compounds were not very different. A greater fraction of the injected dose of ester was excreted in bile than in urine, whereas the opposite was true for MTX. This was consistent with the idea that hepatic extraction is favoured for the lipophilic diester derivative in comparison with the more water-soluble parent acid. 

The intravenous clearance of propranolol is approximately 1.05 L/min. Assuming that the average liver blood flow is approximately 1.5 L/min, we can determine that the hepatic extraction for propranolol (E ) is 0.7 and that the fraction absorbed (F) is 0.3. This means that even though... 

A second in vivo model system that is very useful in sorting through problem of low oral bioavailability is portal vein carmulated animals. There are two ways this experiment can be conducted to determine hepatic extraction (1) measure systemie plasma concentration after oral, portal vein and systemic administration and (2) measure portal vein and hepatic vein concentrations after an oral dose. Both methods yield information on hepatic extraction and the percentage of dose reaching the portal circulation (the product of the fraction absorbed and the fraction metabolized by the gut wall). 

Warfarin enantiomers are extensively metabolized by liver, possess a low hepatic extraction ratio, and are extensively bound (> 99%) to plasma proteins (Table 3). Therefore any change in the protein binding of warfarin enantiomers may alter the clearance and plasma concentrations of R- and S-warfarin [54]. Yacobi and Levy [54] studied the plasma protein binding of racemic and individual enantiomers of warfarin in human blood. The free fraction of R-warfarin was significantly (32%) larger than that of S-warfarin (Table 3). The authors concluded that the difference in the potency of warfarin enantiomers could not be solely explained by the observed differences in the protein binding of the individual enantiomers but rather by the intrinsic ability of R- and S-warfarin for interactions with extravascular receptors. 

E the hepatic extraction ratio for a dmg it is the fraction drug metabolized (and eliminated) by the liver during a single pass through the liver f fraction of an oral dose absorbed from the gastrointestinal tract into the portal (not the systemic) circulation affected predominately by dissolution of dmg in the gastrointestinal tract... 

Pick s ffrst law law that governs the rate of diffusion across a membrane first-order process a process whose rate is directly proportional to the current amount of the compound being transferred by the process linear elimination pharmacokinetic is an example of a first-order process first pass effect the situation whereby the fraction of a dose of orally administered drug that reaches the systemic circulation is equal to 1 minus its hepatic extraction ratio formulation a dosage form of a particular drug... 

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