Liver extraction ratio

To further investigate the role of the liver in brevetoxin metabolism, PbTx-3 was studied in the isolated perfused rat liver model (27, 28). Radiolabeled PbTx-3 was added to the reservoir of a recirculating system and allowed to mix thoroughly with the perfusate. Steady-state conditions were reached within 20 min. At steady-state, 55-65% of the delivered PbTx-3 was metabolized and/or extracted by the liver 26% remained in the effluent perfusate. Under a constant liver perfusion rate of 4 ml/min, the measured clearance rate was 0.11 ml/min/g liver. The calculated extraction ratio of 0.55 was in excellent agreement with the in vivo data. Radioactivity in the bile accounted for 7% of the total radiolabel perfused through the liver. PbTx-3 was metabolized and eliminated into bile as parent toxin plus four more-polar metabolites (Figure 3). Preliminary results of samples stained with 4-(p-nitrobenzyl)-pyridine (29) indicated the most polar metabolite was an epoxide. 

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

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

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) ... 

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). 

---