Restrictively Metabolized Drugs ER

Effect of Changes in Protein Binding on Hepatic Clearance 

Effect of Changes in Intrinsic Clearance on Hepatic Drug Clearance 

Few drugs exhibit an intermediate extraction ratio. Evaluation of the hepatic clearance of these drugs requires consideration of all of the parameters included in Equation 7.6. Disease-associated or drug-induced alterations in protein binding, hepatic blood flow, or intrinsic clearance may alter hepatic clearance significantly. 

Because nonrestrictively metabolized drugs have an extraction ratio that exceeds 0.7, they undergo extensive first-pass metabolism, which reduces their bioavailability after oral administration (Chapter 4). If there is no loss of drug due to degradation or metabolism within the gastrointestinal tract or to incomplete absorption, the relationship between bio-availability (f) and extraction ratio is given by the following equation  

Because Equation 7.8 implies that ER = 1 for nonrestrictively metabolized drugs, yet the oral route of administration can be used for many drugs in this category (e.g., f 0 for morphine and propranolol), it is apparent that Equation 7.9 represents only a rough approximation. By using Equation 7.5 to substitute for ER in Equation 7.9, we obtain a more precise estimate of the impact of first-pass metabolism on bioavailability  

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