Hepatic Organ Clearance Well Stirred Model

GK

LIVER

Cî«/

CLint r

RESERVOIR

(BODY)

Figure 1.8. Simple physiological model of hepatic organ clearance.

Figure 1.8. Simple physiological model of hepatic organ clearance.

Cin is the concentration entering liver or organ Cout is the concentration exiting the liver or organ Q is the hepatic blood flow CLint is the intrinsic metabolic CL

Hepatic CL is defined as:

where E is the extraction ratio and fu is the unbound fraction.

The extraction ratio is the fraction of drug removed by the liver with each pass through the liver. For example, an E of 0.5 means that 50% of the drug passing through the liver is removed.

For drugs with HIGH intrinsic CL, hepatic CL is dependent on hepatic blood flow.

fu X CLint approaches

For drugs with LOW intrinsic CL, hepatic CL is dependent on unbound fraction and intrinsic CL.

fu x CLint approaches CLhepatic — Q7 TTf ,, ^ CLhepatic ~ fu x CLint (1.30)

Since drugs are commonly cleared by the liver, hepatic CL often approximates total body CL and can be categorized based upon a percent of hepatic blood flow.

LOW clearance <30% of hepatic blood flow

MODERATE clearance 30-70% of hepatic blood flow HIGH clearance >70% of hepatic blood flow

LOW clearance <30% of hepatic blood flow

MODERATE clearance 30-70% of hepatic blood flow HIGH clearance >70% of hepatic blood flow

Examples of LOW, MODERATE, and HIGH clearance com

pounds are as follows:

LOW

MODERATE

HIGH

Carbamazepine

Aspirin

Alprenolol

Diazepam

Codeine

Cocaine

Ibuprofen

Cyclosporine

Meperidine

Nitrazepam

Ondansetrone

Morphine

Paroxetine

Nifedipine

Nicotine

Salicylic acid

Nortriptyline

Nitroglycerine

Warfarin

Propoxyphene

Verapamil

Adapted from Rowland and Tozer (2011)

Clearance Estimate is Higher than Hepatic Blood Flow

Categorization of CL as low, moderate, and high based upon hepatic blood flow is important in the assessment of the pharmacokinetics of drugs and drug candidates. Most drugs are orally administered and compounds with low hepatic CL result in better F% and oral exposure. Sometimes certain compounds will show CLs higher than hepatic blood flow. Three possible physiological reasons for this phenomenon include:

1. Compound is cleared by extrahepatic elimination pathways. Although hepatic metabolism is the most common route of drug elimination, it is not the only route.

2. Plasma CL is often estimated rather than blood CL (blood bioanalytical assays are much more difficult to perform than plasma assays). For compounds that preferentially distribute into red blood cells, the estimate of total body CL will be overestimated by the plasma CL. This can be investigated by measuring the blood to plasma ratio of the compound of interest.

Continued

3. Compounds that are given intravenously and have extensive lung uptake can sometimes have CL estimates that are greater than the cardiac output.

Finally, compound degradation in blood or plasma can result in an overestimation of CL. In some cases, CL estimates for compounds cleared by liver may be higher than hepatic blood flow because of instability in plasma/blood.

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