What does intrinsic clearance mean?

What does intrinsic clearance mean?

Intrinsic clearance is the ability of the liver to remove drug in the absence of flow limitations and binding to cells or proteins in the blood.

What is a high intrinsic clearance?

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.

How do you get intrinsic clearance?

Intrinsic clearance (CLi) relates to hepatic extraction (E) and hence systemic clearance CLs and hepatic first-pass effect (F):[1]E=fu⋅CLi/fu⋅CLi+QH where fu is fraction unbound in blood and QH is liver blood flow.

What is in vitro intrinsic clearance?

When implementing IVIVE, microsomes or hepatocytes can be used to determine an in vitro intrinsic clearance (CLint). The in vitro value is then scaled to an in vivo CLint using physiologically based parameters such as microsomal protein content/hepatocellularity and liver weight.

What is intrinsic liver disease?

Intrinsic DILI refers to liver toxicity induced by a drug in a predictable and dose-related manner (e.g., acetaminophen [APAP]); idiosyncratic DILI, which occurs less frequently, is associated with a less consistent dose-toxicity relationship and a more varied presentation.

What does low extraction drug mean?

a) for drugs with low extraction ratio: only unbound drug penetrates membranes and is available for elimination. An increase of the unbound fraction will thus proportionally increase the clearance. Therefore, the unbound drug concentration remains constant and no adaptation of the dosage regimen is required.

How many half lives does it take to clear a drug?

Thus, it follows that after 4 to 5 half-lives, the plasma concentrations of a given drug will be below a clinically relevant concentration and thus will be considered eliminated.

What is KM drug?

Km is a measure of the affinity of the substrate for the enzyme. In pharmacokinetic terms, v is equivalent to the rate of elimination (v = Cu x CL) and S is equivalent to the unbound drug concentration (Cu).

What does metabolically stable mean?

Metabolic stability refers to the susceptibility of compounds to biotransformation in the context of selecting and/or designing drugs with favourable pharmacokinetic properties.

What is VZ in PK?

Vz is the apparent volume of distribution during the terminal phase, i.e. the total amount in the body divided by the plasma concentration (=central. compartment concentration) during the terminal phase.

What is the importance of extraction ratio?

An extraction ratio close to 1 indicates that most of the drug is eliminated during a single pass through the organ. The organ clearance (mainly the hepatic or the renal clearance) may be influenced by the organ blood flow, protein binding and the intrinsic ability of the organ to eliminate the drug.

What does it mean if a drug has a half-life of 4 hours?

The half-life of a drug is the time it takes for the amount of a drug’s active substance in your body to reduce by half. This depends on how the body processes and gets rid of the drug. It can vary from a few hours to a few days, or sometimes weeks.

What is Km and Vmax in pharmacokinetics?

constant and Vmax is the maxi- mum rate of metabolism. Km is the substrate concentration at half the maximum velocity (Vmax).

How do you increase metabolic stability?

One strategy for improving the metabolic stability of a compound is to reduce the overall lipophilicity (e.g. logP, and logD) of the structure. This is because the binding site of metabolizing enzymes is generally lipophilic in nature and hence these enzymes more readily accept lipophilic molecules.