It is the maximum ability of the liver to eliminate the drug in absence of any flow limitation. It has units of volume/time. Based on this definition the hepatic clearance can be as high as the intrinsic clearance but it cannot be higher than it.
The hepatic intrinsic clearance is a measure of the amount of the enzymes available for drug metabolism. Enzyme induction increases the total amount of enzymes available for drug metabolism leading to higher hepatic intrinsic clearance. On the other hand liver diseases that will alter the ability of the liver to eliminate the drug decrease the hepatic intrinsic clearance.
For low extraction ratio drugs, the hepatic intrinsic clearance is close to the hepatic clearance, and for high extraction ratio drugs the intrinsic clearance is much higher than the hepatic clearance.
Enzyme induction means increasing the metabolic activity of the enzyme system. This can happen by a wide variety of agents known as enzyme inducers. Enzyme inducers usually increase enzyme synthesis leading to higher amount of the enzyme and increase in the capacity of one or more metabolic pathway.
The consequence of enzyme induction on drug metabolism depend on the drug. Some inducers are specific inducers of certain specific sub-family of CYP-450 which can affect the drugs metabolized by that particular CYP-450 sub-family.
Also drugs that are metabolized by high capacity metabolic pathways (high extraction ratio drugs, or drugs that have high intrinsic metabolic clearance) will not be affected significantly by enzyme inducers. On the other hand, enzyme induction significantly affect the rate of metabolism of drugs that have low intrinsic metabolic clearance (low extraction ratio drugs).
The extraction ratio is the fraction of the drug presented to the organ which is eliminated during a single pass through the organ.
The extraction ratio can have values between 0 and 1 (or 0% - 100%). It is zero when the drug is not eliminated by the organ, and it is 1 when all the drug presented to the organ is eliminated during a single pass.
The extraction ratio does not have units.
The total body clearance is the volume of the plasma or blood which is completely cleared from the drug per unit time. It has units of volume/time.
The CLT for a drug is constant within a patient (dose and concentration independent) when the elimination processes follow first-order kinetics.
The total body clearance is a measure of the efficiency of all eliminating organs in eliminating the drug and it is the sum of all organ clearances (i.e. CLT is the sum of the renal clearance, hepatic clearance and all other organ clearances).
The elimination rate constant and the half life (the dependent pharmacokinetic parameters) are dependent on (is determined from) the total body clearance and the volume of distribution (the independent pharmacokinetic parameters).
CLT
Vd = k andCLT
Vd =0.693
t 1/2Bioavallability is a measure of the fraction of the administered dose that reaches the systemic circulation.
Absolute bioavailability is the fraction of the total dose that reaches the systemic circulation. It can have values between zero when the drug is not absorbed at all to 1 when all the administered dose reaches the systemic circulation. The absolute bioavailability can be expressed in terms of percentage (0% - 100%).
The relative bioavailability is the bioavailability of a drug product relative to the bioavailability of another drug product (reference standard preparation). The relative bioavailability can take any value above zero. It can be more than one when the product under investigation has bioavailability higher than that of the reference standard.