Expanded Answers for Study Problems in: Rowland & Tozer's Clinical Pharmacokinetics: Concepts and Applications, 3rd edition.

Chapter 21 - Metabolite Kinetics

Study Problems on Page 390-392

2. Remember that

AUC_(m)/AUC = CL_m/CL_(m)

Where the textbook uses CL_f where I used CL_m. The latter is in keeping with international standards and present less confusion, particularly when there are multiple metabolic pathways for a given agent. From the equation above, you can see that if the metabolite formation pathway were induced (i.e., CL_m were increased) that the ratio of metabolite to parent compound would be increased. Thus, statement (a) is consistent with this observation. On the other hand, neither the volume of distribution nor the fraction absorbed enter into the relationship shown above, indicating these could not explain the increased ratio. Moreover, the increase in an alternative pathway does not effect the ratio since any change in f_m is offset by a corresponding change in CL. Thus, (a) is the only statement consistent with the increased ratio.

7.a) Notice that while there is no sulfated isoproterenol detected in urine after i.v. administration, the O-methylisoproterenol is metabolized to the sulfate conjugate. This suggests the possibility that the sulfate enzymes in the intestine may differ from those in the liver, with differing substrate specificity.

c) The data appear more complicated than the answer given in the text. Note that the total recovery of isoproterenol (determined by adding all species) in urine after oral administration is 75.2%, while after inhalation it is 96.9%. If the metabolic pattern seen after inhalation were due to the fact that much of the dose is swallowed, we would expect the total recovery to be similar with the two routes (The lower urinary recovery of the drug after oral administration is probably explained by some drug never being absorbed and some diffusing back into the lumen after it is sulfated, followed by elimination in the excreta.). On the other hand, the high percentage of drug recovered as the sulfate metabolite suggests metabolism is occurring somewhere other than the liver (since no sulfate metabolite is recovered after i.v. administration). This indicates that the drug undergoes substantial conjugation with sulfation in the pulmonary epithelium. Indeed, numerous studies have shown that the lung can extensively conjugate catecholamines.

9. See Fig. 21-6 on page 376 of the text, which illustrates this principle.

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