By Larry Bauer
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REFERENCES 1. Shargel L, Wu-Pong S, Yu ABC. Applied biopharmaceutics and pharmacokinetics. 5th ed. New York: McGraw-Hill; 2005. 2. Ludden TM, Allen JP, Valutsky WA, et al. Individualization of phenytoin dosage regimens. Clin Pharmacol Ther. 1977;21(3):287–293. 3. Levy G. Pharmacokinetics of salicylate elimination in man. J Pharm Sci. 1965;54(7):959–967. 4. Bowdle TA, Patel IH, Levy RH, et al. Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther. 1980;28(4):486–492.
The hepatic clearance of drugs with low extraction ratios does not change much when liver blood ﬂow decreases secondary to liver or cardiac disease. Examples of drugs with low hepatic extraction ratios are valproic acid, phenytoin, and warfarin. For drugs with high hepatic extraction ratios, hepatic clearance is mainly a function of liver blood ﬂow: ClH = LBF. The rate limiting step for drug metabolism in this case is how much drug can be delivered to the liver because the capacity to metabolize drug is very large.
Once drug molecules are absorbed from the gastrointestinal tract, they enter the portal vein. 5 L/min. If the drug is hepatically metabolized, part of the drug may be metabolized by the liver even though the majority of the drug was absorbed from the gastrointestinal tract. Drugs that are substrates for CYP3A4 and CYP2D6 are particularly susceptible to presystemic metabolism by the liver. Blood leaving the liver via the hepatic vein enters the inferior vena cava, and will eventually be pumped through the lung by the right side of the heart before entering the left side of the heart and being pumped into the arterial system.
Applied Clinical Pharmacokinetics by Larry Bauer