Hepatic extraction ratio

Table 1 Drugs Suspected to Have High Hepatic Extraction Ratios...

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... 

Lau, Y.Y. et al. 2002. The use of in vitro metabolic stability for rapid selection of compounds in early discovery based on their expected hepatic extraction ratios. Pharm. Res. 19 1606. 

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

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. 

Low hepatic extraction ratio and low protein binding to minimize reUance on hepatic blood flow. 

Subsequent high systemic clearance due to a large hepatic extraction ratio each time the plasma recirculates through the liver... 

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). 

Codeine (7.1) is an analgesic that may be administered by an IV bolus (Figure 7.4). A typical therapeutic Cp value for codeine is 200 ng/mL, and the hepatic extraction ratio (Eh) for codeine is 0.50. The clearance of codeine (CEp) is reported to be around 10.7 mL/min/kg, or 750 mL/min, in a 70-kg patient. Codeine is not observed in the urine of patients, so ER must be 0, and renal clearance (CER) is 0 mL/min. As a result, hepatic clearance of codeine (CEH) is equal to total clearance. Because codeine is cleared only by the liver, codeine provides a simple illustration of the ideas surrounding clearance. 

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). 

By use of these basic concepts, Wu et al. [87] conducted an examination of the pharmacokinetics of cyclosporine after administration in the presence of two known CYP3A inhibitors, ketaconazole and erythromycin and the CYP3A inducer rifampin. Alterations to the cyclosporin hepatic extraction ratio were measured in the presence of the inducer/inhibitor, and oral cyclosporin biovailability (relative to IV administration in the presence/absence of the interacting species) was calculated. These data are reproduced in Table 3 and provide several impor-... 

The extent to which the liver successfully eliminates a xenobiotic from the blood is determined by the intrinsic clearance of the liver (Clh) and the rate at which the xenobiotic is presented to it (i.e., the hepatic blood flow Qh ). This gives the overall hepatic extraction ratio (E) for the compound, as shown in Equation 11.3 ... 

Rane, A. et al. Prediction of hepatic extraction ratio from in vitro measurement... 

In liver disease, the likelihood of a pharmacoki-netically relevant drug-disease interaction depends on the type of drug (extent of intra-/extra-hepatic elimination, hepatic extraction ratio, protein binding) and the nature (flow, enzymatic capacity/reserve) and extent of the liver dysfunction. The likelihood of... 

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 ... 

The hepatic extraction ratio (ERh) can be determined after intravenous dosing from the ratio of hepatic clearance (CLh) to hepatic blood flow (2h)-... 

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