Answer to Practice Problem #2 Metabolite Kinetics Tutorial:

            From the data given:

                                                                                                         % excreted in urine as

                                Dose                          Total Clearance (ml/min/kg)            sulfate metabolite                glucuronide metabolite

                                15 mg/kg                                   44                                                        91.9                                                     4.7

                                150 mg/kg                                  9.3                                                      68.6                                                   16.3

 

            Examination of the % excreted in urine by each pathway (sulfation and glucuronidation) may lead one to conclude that the rate of metabolism via sulfation is decreased with increasing acetaminophen dose, while the rate of glucuronidation is increased with increasing acetaminophen dose. However, more careful analysis reveals that the rate of elimination by both sulfation and glucuronidation are reduced with increasing doses of acetaminophen. To analyze the data more carefully, we need to determine the formation (or partial) clearance of acetaminophen via sulfation and glucuronidation.

 

To calculate the formation clearance of each metabolite, recall that CL_m = f_m x CL_t. Thus, the formation clearance of the sulfate metabolite at the 15 mg/kg dose level is given as:

CL_m-sulfate = 0.919 x 44 ml/min/kg = 40 ml/min/kg

           

This is then continued for the rest of the values to be determined, such that

 

Dose               Formation CL of sulfate metabolite              Formation CL of glucuronide metabolite

15 mg/kg                                  40 ml/min/kg                                                           2.0 ml/min/kg

150 mg/kg                                6.4 ml/min/kg                                                      1.5 ml/min/kg

 

From the data above, it is apparent that the formation clearance by both sulfation and glucuronidation are reduced as the dose of acetaminophen is increased – indicating that both pathways are becoming saturated. So why does the % of dose excreted as the glucuronide metabolite increase with the 150 mg/kg dose compared to the 15 mg/kg dose? Notice that the magnitude of decrease in clearance to the sulfate metabolite is decreased to a much greater degree via sulfation (84% reduction) versus that via glucuronidation (25% reduction). Hence, the fraction (or percent) of the dose excreted as the glucuronide metabolite increases, even though the clearance via glucuronidation decreases.

Last revised 07/19/04

 

ã 2004 -  Craig K. Svensson, Pharm.D., Ph.D.

 

Return to the Metabolite Kinetics Tutorial

 

Return to the Index for Lecture Tutorials

 

Return to Pharmacokinetics and Biopharmaceutics Homepage