Answer to Practice Problem #1 Pharmacokinetic Drug Interactions Tutorial:

 

            The first step in solving this problem is to determine whether sumatriptan is a drug with a low or high intrinsic hepatic clearance. It is states that the total clearance if 19 mL/min/kg and that 22% of the drug is eliminated renally, the rest by hepatic metabolism. Thus, the fraction eliminated by hepatic elimination is 0.78. From this we can determine the average hepatic clearance:

CL_H = 0.78 x 19 mL/min/kg = 14.82 mL/min/kg

           In an average 70 kg male

CL_H = 14.82 mL/min/kg x 70 kg = 1037.4 mL/min

    

           You will note that this value is in the range of normal hepatic blood flow. Therefore, we conclude that sumatriptan is a drug that displays a high intrinsic hepatic clearance.

           From this knowledge, we can know determine the impact of an inducer on the various pharmacokinetic parameters.

 

AUC_oral = Do/(f_ubCL_uint)   Therefore, an increase in the unbound intrinsic hepatic clearance (the consequence of an inducer), would result in a decrease in this value.

 

Since this is a high intrinsic hepatic clearance drug, CL_H ~ Q_H. Thus, a change in enzyme activity resulting from administration of an enzyme inducer would not change the hepatic clearance of this drug.

 

Since V_ss is not influenced by enzyme activity, it would not change in the presence of an enzyme inducer.

 

Since t_1/2 is a function of CL_H and V_ss, and these parameters remain unchanged, the t_1/2 would not change with addition of an enzyme inducer.

 

C_max after oral administration is a function of the rate of absorption, the rate of elimination, and the effective dose (F x Dose). We have already stated that the elimination rate does not change, nor would we expect any change in the rate of absorption with administration of an inducer. However, the first-pass effect will be increased, resulting an a reduced systemic availability. Therefore, the C_max after oral administration will decrease.

 

Last revised 07/13/05

 

ã 2005 -  Craig K. Svensson, Pharm.D., Ph.D.

 

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