PHARMACOKINETICS AND bIOPHARMACEUTICS (46:138)

LECTURE TUTORIAL

Metabolite Kinetics

 

Key Terms:

 

Formation rate-limited disposition: The condition in which the elimination of a metabolite is faster than that of the parent compound, such that the disposition of the metabolite is dependent upon the rate of its formation. This is because the slowest step in the metabolic scheme (slide 5 of the lecture) is the elimination of the parent compound (or the formation of the metabolite)[i.e., k_m<k_(m)].

 

Elimination rate-limited disposition: The condition in which the elimination of a metabolite is slower than that of the parent compound, so that the disposition of the metabolite is dependent upon the elimination rate of the metabolite. This occurs due to the fact that the slowest step in the metabolic scheme is then elimination of the metabolite (i.e., k_m > k_(m)).

 

Metabolic interconversion: This occurs when a metabolite is converted back to the parent compound in vivo. This can be particularly important in the presence of impaired renal function, where substantially more of the metabolite may accumulate (resulting in more conversion back to the parent compound) than in the presence of normal renal function.

 

Key Principles:

 

When the metabolite is the active species, the kinetics of the metabolite will determine the time course of pharmacologic effect. Understanding the kinetics of the metabolite is important because often it is the metabolite of the drug that is the active species. In this situation, the duration of action, for example, will be determined by the half-life of the metabolite.

 

We do not need to be concerned about metabolite accumulating when the metabolite exhibits formation rate-limited disposition. In this situation, metabolite will not accumulate at a rate that differs from the parent compound. Therefore, we can dose the drug based upon the disposition parameters for the drug and not directly concern ourselves with the parameters for the metabolite … even if the metabolite is the active species.

 

When an active metabolite displays elimination rate-limited disposition, dosing based upon the pharmacokinetics of the parent drug may lead to accumulation of the metabolite and toxicity. When a metabolite exhibits elimination rate-limited disposition, the half-life of the metabolite is longer than that of the parent drug. This means the time to achieve steady-state for the metabolite will be longer for the metabolite than the drug. Hence, dosing based upon the disposition of the parent drug will result in an accumulation of the metabolite and may result in toxicity. On the other hand, when an active metabolite exhibits elimination rate-limited disposition, the drug does not have to be administered as frequently as would be anticipated based upon the kinetics of the parent compound.

 

Formation of the metabolite during first-pass can alter the appearance of the concentration versus time curve for a metabolite that displays formation rate-limited disposition. When a metabolite that is formed during first-pass metabolism after oral administration, there is essentially a ‘bolus’ dose of the metabolite that enters the systemic circulation from being formed during the first-pass. This ‘bolus’ of metabolite appears to decline in concentration faster than that seen later with the metabolite formed from systemic circulation of the parent compound. One can view the ‘bolus’ of metabolite as being eliminated in a manner dependent upon the true elimination rate of the metabolite, whereas the metabolite formed via the systemic circulation displays formation rate-limited elimination. This results in an apparent bi-exponential decline in the metabolite concentrations after the oral administration of parent drug.

 

           

Practice Problems:

 

1.       Drug A and B are both drugs that give rise to active metabolites and both drugs are used as analgesics. The active metabolite of Drug A exhibits formation rate-limited disposition, while the active metabolite of Drug B exhibits elimination rate-limited disposition. The half-life of Drug A and Drug B are found to be identical. Which would produce the longest duration of action, administration of Drug A or Drug B?   Answer

 

        2.    Galinsky and Levy (JPET 219:14, 1981) examined the dose dependence of acetaminophenelimination in rats. Acetaminophen is eliminated in urine unchanged, as well  

                       both glucuronide and sulfate metabolites. Below are the mean data from their study after a dose of 15 or 150 mg/kg of acetaminophen intravenously.

 

                                                                                                         % 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

 

                      From this data, determine whether the rate of metabolism via glucuronidation and sulfation is increased or decreased as the dose of acetaminophen is increased. Answer 

 

 

 

 

 

 

                            

 

 

Last revised 07/19/04

 

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

 

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