Chapter 17

Metabolism

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Systemic Availability

Even if we can assume that a drug is completely absorbed across the G-I tract, a proportion of the dose may be eliminated by the liver before reaching the systemic circulation because of the anatomical arrangement of the portal circulation. This pre-systemic or first-pass elimination can be determined from the extraction ratio, E, such that the fraction of the dose that is available to the central circulation is 1-E. This 1-E value becomes the maximum availability possible before allowing for reduced product performance.

For drugs which are extensively metabolized, first pass metabolism can be quite important. It means that higher doses must be given orally compared with parenteral administration.

For example morphine PO 30 mg, cf. IV 5 mg and lidocaine not active PO

In liver disease there is potential for changing the systemic availability of high extraction drugs and thereby affecting steady state concentrations.

If liver disease causes a modest reduction in the extraction ratio, from for example 0.95 to 0.9, the fraction of the orally administered drug reaching the systemic circulation (1-E) will be doubled. One of the consequences of the pathogenesis of chronic liver disease is the development of porta-systemic shunts that may carry drug absorbed from the G-I tract through the mesenteric veins directly into the systemic circulation. Thus in a disease where biochemical hepatic function is relatively well maintained (e.g., schistosomiasis), oral treatment with high clearance drugs such as morphine or propranolol can lead to high blood levels and an increase in adverse drug effects. For example, 30 mg morphine orally may act like 30 mg IV and lead to over dosage toxicity.

Pharmacokinetics of Drugs in Patients with Liver Disease

Liver disease can have a profound effect on the patient's physiology which in turn can influence drug pharmacokinetics. Using the venous equilibration model presented on the previous page we can expect changes in fu, Q and CLint to influence the overall pharmacokinetics of a drug. This can be due to changes in protein binding (Chapter 18), to reduced enzymatic activity of the liver cells or reduced ability of the drug to reach the enzymes present in liver cells.

Decreased protein binding appears to be more common in chronic liver disease (such as cirrhosis) compared with more acute diseases (such as viral hepatitis). Some examples include morphine (15%), propranolol (38%), diazepam (70-200%), phenytoin (40%) and tolbutamide (30%) (Benet et al. 1984 t70).

A number of high extraction ratio (flow limited) drugs exhibit increased oral bioavailability, decreased clearance or increased half-life. Some examples include chlormethiazole (F increased 1000% and decreased clearance), lidocaine (decreased clearance), meperidine (increased F and t1/2 with decreased clearance), propranolol (increased F and t1/2) and verapamil (increased F and t1/2 and decreased clearance) (Benet et al. 1984 t67).

Capacity limited (poorly extracted) drugs also have altered pharmacokinetic parameters in patients with liver disease. Examples include ampicillin (increased t1/2), diazepam (increased t1/2 and decreased clearance), theophylline (increased t1/2 and decreased clearance) and tolbutamide (increased t1/2 and decreased clearance) (Benet et al. 1984 t68-9).

Pharmacogenomic Considerations

Enzymes are produced according to the genetic make-up of the individual. This means that different individuals may produce more or less of a particular enzyme but it also means that different forms (allele variants) of the enzyme may be produced by different individuals. Enzymes control the metabolism of many drugs and different forms of these enzymes will cause differences in the pharmacokinetics of the drugs. Some enzymatic forms are more active, others less active. One example is the enzyme CYP2C9 and its influence on warfarin pharmacokinetics (that is, the five times more active S-form). There are three forms of CYP2C9; *1, *2 and *3. The CYP2C9*1 is the wild form and the most common. However, there are 10% and 8% of population with the *2 and *3 forms, respectively. Both these variants result in reduced enzymatic activity or reduced drug clearance. One study (Higashi et al 2002) indicated that the daily maintenance dose ranged from 5.6 mg (*1/*1) to 1.6 mg (*3/*3) with different individuals. These studies suggest the potential for more difficult stabilization of the required dose and higher incidence of bleeding.
References


Student Objectives for this Chapter

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