Extraction ratios, bioavailability

This indicates that the first-pass availability is a function of organ flow, protein binding, and intrinisic clearance of the organ. When fu CLint Q (i.e., when we have relatively large extraction ratios), the first-pass bioavailability is equal to... 

Under this circumstance, the first-pass bioavailability is inversely proportional to the unbound fraction, and changes in the binding are expected to have a significant effect. It is also clear that changes in both the blood flow and the intrinsic clearance of the first-pass organ may have a significant effect when the extraction ratio is high (fu CL n Q). On the other hand, if... 

The expression of a significant gut wall first-pass extraction ratio has several implications for affected drugs. First, oral bioavailability is lower than would be expected from the extent of absorption and the hepatic first-pass extraction. Second, the variability in expression of gut wall metabolic enzymes and transporters can lead to significant variability in gut wall first-pass extraction and thus oral bioavailability. Finally, the site of expression of these enzymes and transporters (i.e., the villus tip) brings them into contact with potentially co-administered drugs or dietary constituents, which could be inhibitors or inducers. Thus, there is the potential for drug-drug interactions at the level of the gut wall. 

With this experimental set-up, absolute bioavailability and hepatic extraction ratio ( h) can be directly calculated as per Eqs. 2.32 and 2.33 ... 

Following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme system) or even in the portal blood, but most commonly it is the liver that is responsible for metabolism before the drug reaches the systemic circulation. In addition, the liver can excrete the drug into the bile. Any of these sites can contribute to this reduction in bioavailability, and the overall process is known as first-pass elimination. The effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio (ER) ... 

The systemic bioavailability of the drug (F) can be predicted from the extent of absorption (f) and the extraction ratio (ER) ... 

A drug such as morphine is almost completely absorbed (f = 1), so that loss in the gut is negligible. Flowever, the hepatic extraction ratio for morphine is 0.67, so (1 - ER) is 0.33. The bioavailability of morphine is therefore expected to be about 33%, which is close to the observed value (Table 3-1). 

In this application, the use of wild-type electric eel AChE and a recombinant AChE, specifically selected as very sensitive to dichlorvos, was compared. The effect of the matrix extract was determined by using various sample solvent ratios, 1 2.5, 1 5, 1 10, and 1 20. The optimal extraction ratio, considering the electrochemical interferences and the effect on enzyme activity and bioavailability of the pesticide, was 1 10. 

If an oral drug is fully absorbed, then its bioavailability depends on its resistance to first-pass metabolism by the liver. Therefore, the hepatic extraction ratio (fin) determines the bioavailability of fully absorbed oral drugs (Equation 7.24). 

For drugs with a low extraction ratio, oral bioavailability is typically high, as most of the dose will be unaffected by the liver on first pass. Consequently, changes in extraction ratio are unimportant. For example, if hepatic disease caused a fall in extraction ratio from 0.1 to 0.05, bioavailability would only increase from 90% to 95%, which is unlikely to be clinically significant. 

Varices indicate that portal vein blood flow has been diverted away from the liver secondary to portal hypertension. This would have a significant impact on first-pass metabolism, increasing the bioavailability of oral drugs that are usually extensively cleared on first pass through the liver, i.e. those with a high extraction ratio (>0.7). 

Does the drug have a high extraction ratio (>0.7) such that bioavailability may be affected by portal hypertension/varices causing reduced or absent first-pass metabolism ... 

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... 

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