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    Hepatic clearance

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    142 views3 pages

    Hepatic Clearance

    Uploaded by

    Miami Arif

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Flag for inappropriate content
    of 3

    Hepatic clearance

    Hepatic clearance quantifies the loss of drug during its passage through the liver. Hepatic clearance
    results from hepatic metabolism and biliary excretion and is a function of the hepatic blood flow,
    the drug plasma protein binding and the activity of liver enzymes and transporters. Variation of one
    of these parameters may more or less influence the hepatic clearance of a drug, depending on its
    hepatic extraction ratio.
    Variation of liver enzyme activity mainly affects the hepatic intrinsic clearance. This is the main
    source of interindividual variation of hepatic clearance.
    Oral bioavailability is related to the hepatic extraction ratio. The higher the extraction ration, the
    higher the hepatic first past effect and the lower the bioavailability.
    The two major determinants of hepatic clearance are the efficiency of drug removal from the blood
    and the efficiency of blood delivery to the liver. The former is described by the hepatic extraction
    ratio, and the latter is simply the blood flow to the liver. Thus, the equation below is basically "flow
    times extraction ratio".

    Hepatic extraction ratio


    An important factor which affects the hepatic extraction ratio is protein binding. Hepatocytes only
    have access to the free unbound fraction of the drug and the hepatic extraction ratio equation reflects
    that fact:

    Intrinsic clearance
    In other words, the intrinsic clearance is the raw metabolising power of the hepatocytes. If the intrinsic
    clearance for a drug is very high, its metabolism by the liver is limited by hepatic blood flow (i.e. the
    liver can only crack as many molecules as are presented to it). If the drug has an extremely low
    intrinsic clearance, hepatic blood flow will have minimal influence on its metabolic rate (the
    hepatocytes won't work any harder no matter how much drug you present to them).
    Intrinsic clearance is described by the following equation:
    The relationship works like this. With a low intrinsic clearance rate, the extraction ratio drops
    dramatically whenever the hepatic blood flow increases. This basically means that increasing the hepatic
    blood flow has minimal positive effect on the total clearance of the drug.
    With a high intrinsic clearance, the hepatic metabolism is highly effective at removing the drug from the
    circulation. Increased blood flow will increase the delivery of the substrate to the enzyme system, and
    the enzyme system will cope admirably. As a result, the extraction ratio drops minimally, and the
    hepatic clearance of the drug increases in proportion to the increased blood flow. The higher the
    intrinsic clearance, the more linear this relationship.

    Examples of drugs with different hepatic clearance profiles

    The drugs with a high extraction ratio will have their total hepatic clearance highly dependent on hepatic
    blood flow, and in low flow states their metabolism will suffer. Drugs with a low extraction ratio will be
    limited mainly by the uselessness of hepatic enzymes, and their metabolism will be largely unchanged in
    low flow states. Generally, one can guess when a drug is going to have a low hepatic extraction ratio
    from the fact their pharmacokinetics are either non-linear or zero-order, reflecting the fact that their
    metabolic enzymes reach their saturation point (Vmax) at a low concentration.
    Clinical implications
    If the liver is the most important organ for the elimination of a drug, it is essential to know whether the
    drug has a high or low hepatic extraction ratio: it determines dosage adaptations in patients presenting
    conditions altering:
    1. Hepatic blood flow (e.g. congestive heart failure)
    2. Plasma protein binding (e.g. hypoalbuminemia, displacement by other drugs)
    3. Hepatic enzymatic activity (e.g. liver failure, specific inhibition or induction by drugs,
    genetic polymorphism)

    Thank you…

    By: Momin Faris, Miami Arif & Noor Mohammed


    Group: B

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