A large, multinational drug corporation conducts a phase I clinical trial to evaluate the safety profile and pharmacokinetic properties of a new drug designed to treat refractory epilepsy. Initial studies in animals showed that the drug undergoes extensive metabolism by the liver into glucuronidation byproducts that are primarily excreted by the kidneys. The curve below demonstrates the glucuronidation rate of the drug over a wide range of doses. Which of the following is the most accurate statement about this drug's metabolism?

Question

A large, multinational drug corporation conducts a phase I clinical trial to evaluate the safety profile and pharmacokinetic properties of a new drug designed to treat refractory epilepsy.  Initial studies in animals showed that the drug undergoes extensive metabolism by the liver into glucuronidation byproducts that are primarily excreted by the kidneys.  The curve below demonstrates the glucuronidation rate of the drug over a wide range of doses.  Which of the following is the most accurate statement about this drug's metabolism?

Quizplus · Accepted Answer

11ec160b_3c2c_c17d_9249_7d01b365689d_MD0001_00 The drug under investigation is glucuronated by the liver into water-soluble byproducts that can then be excreted by the kidney. The graph above shows how the rate of drug glucuronidation changes with increasing drug doses. At lower doses, the quantity of drug-glucuronide formed is directly proportional to the dose administered (ie, as more of the drug is administered, more drug-glucuronide is produced). Because a fixed proportion of drug is converted to the metabolite, this early portion of the graph represents first-order kinetics. As the active sites on glucuronosyltransferase become saturated, the drug-glucuronide rate does not continue to rise with increasing doses of the substrate drug. At this point (2 on the graph), the kinetics change from first- to zero-order kinetics and the graph levels out to a zero slope. With zero-order kinetics, a constant amount of drug is metabolized and eliminated per unit of time regardless of its concentration or dose. Zero- and first-order kinetics can also be represented graphically by showing the decrease in drug concentration over time after a single dose. Zero-order metabolism is indicated by a straight line with negative slope (fixed amount eliminated per unit of time), whereas first-order kinetics manifest as an exponential decay curve (fixed proportion eliminated per unit of time). (Choice A) After point 3, the curve remains flat, indicating that a constant amount of drug is metabolized per unit of time regardless of the dose. As higher doses are administered, the proportion that is converted to the metabolite becomes smaller (ie, the proportion metabolized is non-constant after point 3). (Choice B) Bioavailability is the fraction of an administered drug that reaches the systemic circulation unchanged. It usually decreases with oral administration due to incomplete absorption and first-pass metabolism compared to parenteral administration. In this case, higher doses of the drug are likely to have greater bioavailability due to the saturation of hepatic metabolism. (Choice C) At point 2, biotransformation (ie, metabolism) of the drug begins to switch from first-order to zero-order kinetics due to enzyme saturation. However, drug metabolism does not stop. (Choice E) Before point 1, drug metabolism proceeds via first-order kinetics. Therefore, the drug metabolization rate increases as higher doses are administered. Educational objective: In first-order kinetics, a constant fraction (or proportion) of drug is metabolized per unit of time, so the amount metabolized changes based on the serum concentration. In zero-order kinetics, a constant amount of drug is metabolized per unit of time, independent of serum levels.

A Large, Multinational Drug Corporation Conducts a Phase I Clinical