Transcript
0:00Hepatic clearance and extraction
Lesson 4.5 of our metabolism module: hepatic extraction. Metabolism is the chemical change of a drug by enzymes, and it usually ends the drug action. For many drugs, it is the main route of elimination, the irreversible loss of the unchanged drug from the body. The liver carries out much of this metabolism. Clearance is the volume of blood or plasma from which the body removes all of the drug per unit of time. Hepatic clearance is the clearance by the liver. The extraction ratio is the fraction of the drug that enters the liver and that the liver removes in one pass of the blood. A ratio of 1 means complete removal in one pass, and a ratio of 0 means no removal.
0:59Three quantities
In the usual model, three quantities set the extraction ratio. The first is hepatic blood flow, the volume of blood that passes through the liver per unit of time. It delivers the drug to the liver. The second is the unbound fraction in blood, the concentration of drug that is not bound to proteins, divided by the total concentration in blood. Only unbound drug is available to the liver enzymes. The third is intrinsic clearance, the rate of metabolism in the liver divided by the unbound drug concentration at the enzymes. It measures the ability of the liver to eliminate the drug, mainly by its enzymes, with no limit from hepatic blood flow or protein binding.
1:56The well-stirred model
The well-stirred model combines the three quantities in one equation. Hepatic clearance from blood equals hepatic blood flow times the extraction ratio. The model gives the extraction ratio as a fraction. The numerator is the product of the unbound fraction and intrinsic clearance. The denominator is the sum of that product and hepatic blood flow. The model treats the liver as one space in which the drug mixes completely. The unbound drug concentration at the enzymes therefore equals the unbound concentration in the blood that leaves the liver.
2:43High- and low-extraction drugs
Two cases follow from the equation. The first is a high-extraction drug, for which the product of the unbound fraction and intrinsic clearance is much larger than hepatic blood flow. Hepatic clearance then approaches hepatic blood flow, and the extraction ratio approaches 1. The clearance therefore depends mainly on hepatic blood flow, and a small change in intrinsic clearance or the unbound fraction has little effect on it. The second is a low-extraction drug, for which that product is much smaller than hepatic blood flow. Hepatic clearance then approaches the product itself, and the extraction ratio is small. The clearance therefore changes in proportion to the unbound fraction and to intrinsic clearance, and hepatic blood flow has little effect on it.
3:45Lidocaine
Lidocaine and warfarin show the two cases. Lidocaine is a high-extraction drug: in six healthy adults who received lidocaine by infusion into a vein, the extraction ratio was 0.86. In these adults, the liver removed 86 percent of the lidocaine that entered it in one pass. The product of the unbound fraction and intrinsic clearance was 8.19 liters per minute. This is more than six times the hepatic blood flow in the same adults. In the infusion study, the adults also received the beta-blocker propranolol, a drug that blocks the beta receptors for adrenaline. Three days of propranolol lowered hepatic blood flow from 1,275 to 957 milliliters per minute, by 25 percent. The product changed from 8.19 to 9.50 liters per minute, which the authors report as no statistically significant change. With less hepatic blood flow and no significant change in the product, the extraction ratio rose from 0.86 to 0.90, as the equation predicts. The lidocaine clearance from plasma fell less, from 1,030 to 866 milliliters per minute, or by 16 percent. Propranolol therefore lowered the clearance of lidocaine mainly through its effect on hepatic blood flow, as the model predicts for a high-extraction drug.
5:39Warfarin
Warfarin is a low-extraction drug, and the liver metabolizes almost all of it. Its clearance is about 3.3 milliliters per minute in a 70 kilogram adult. This is small compared with the hepatic blood flow of 1,275 milliliters per minute in the lidocaine study. The extraction ratio is therefore below 0.01, and the liver removes less than 1 percent of the warfarin in one pass. Plasma proteins, mainly albumin, bind 97 to 99 percent of the warfarin in plasma, and only 1 to 3 percent is unbound. CYP2C9, a cytochrome P450 enzyme, metabolizes most of S-warfarin, the more potent of its two mirror-image forms. A change in CYP2C9 activity changes the clearance of warfarin and its unbound concentration. The total clearance is the clearance calculated from the total plasma concentration, bound plus unbound. A change in the unbound fraction changes the total clearance, and the faster or slower elimination offsets most of the change in the unbound concentration.
7:10Summary
In summary, in the usual model, hepatic clearance depends on hepatic blood flow, the unbound fraction in blood and intrinsic clearance. The well-stirred model combines the three in one equation. The extraction ratio shows whether hepatic blood flow or the other two quantities mainly limit the clearance. For lidocaine, with an extraction ratio of 0.86, the clearance depends mainly on hepatic blood flow. Propranolol lowered both the hepatic blood flow and the clearance. For warfarin, a low-extraction drug, the total clearance changes with CYP2C9 activity and the unbound fraction, but the unbound concentration changes mainly with CYP2C9 activity. This concludes lesson 4.5 on hepatic extraction.
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Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
