Answer to Practice Problem #2 Hepatic Clearance Tutorial:
In order to answer this question, you need to determine whether the drug exhibits a high or low hepatic clearance. Based upon the data in the table given, >90% of valproic acid is excreted in the urine as metabolites. That would suggest that >90% of the elimination of the drug is via liver metabolism. Since the total clearance of the drug is stated to be10 mL/hr/kg, the average hepatic clearance for the drug in the average male (70 kg) will be 700 mL/hr. To compare this to hepatic blood flow, we convert it to L/min, such that
CLT = 700 mL/hr x 1hr/60 min = 12 mL/min x 1 L/1000 mL = 0.012 L/min
The CLT for valproic acid is substantially less than the average hepatic blood flow (1.0 – 1.5 L/min). Hence, the drug must be a low hepatic clearance drug. Knowing this, we can now predict the impact of adding a drug that displaces valproic acid from protein binding sites (i.e, increases fup). For a low clearance drug,
CLH ~ fubCLuint
Thus, an increase in fub will result in an increase in CLH. What effect will this have on the steady-state concentration of total drug?
Css = Ko/CLH
Clearly, an increase in the hepatic clearance while dosing rate (Ko) remains constant will result in a decrease in the steady-state concentration of total drug. But what will happen to the steady-state concentration of free drug? There are several ways to look at this. First, recognize that
Css = Ko/( fubCLuint)
Moreover,
Cfubss = fubCss or Css = Cfubss/fub
Substituting for Css
(Cfubss/fub) = Ko/( fubCLuint)
Simplifying,
Cfubss = Ko/CLuint
Thus, the steady-state concentration of free drug will not be changed by alterations in protein binding, since such changes do not alter Ko or CLuint.
Last revised 07/13/05
ã 2005 -
Craig K. Svensson, Pharm.D., Ph.D.
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