Answer to Practice Problem #1 for Determinants of Drug Disposition Tutorial:

As can be seen from the above graph, the appearance of drug in the body would be quicker after chewing the tablet compared to swallowing the tablet whole. This is because chewing accelerates the process of disintegration – which is the slowest step for this drug product. As a consequence, drug concentration will reach the minimum effective concentration more quickly and result in a reduced onset time. The peak concentration is also higher. Remember that the peak concentration of a drug is a function of the rate of absorption and the rate of elimination.* Since the rate of elimination would not change in this example, increasing the rate of absorption will result in a higher peak concentration after chewing the tablet. This will cause a greater intensity of effect. While perhaps not as obvious, it would also be anticipated that the period of time during which the concentration of drug is above the minimum effective concentration will be greater after chewing the tablet – causing a longer duration of action for the drug.

 

*What … you don’t remember this from Pharmaceutics II?! Relax, I’ll explain it for you. When drug is absorbed from the gastrointestinal tract, it enters into the body causing a rise in the concentration of drug in blood. But as soon as it reaches the blood, some of it is distributed to organs that eliminate the drug from the body (such as the liver or the kidneys). Thus, absorption causes an increase in the concentration, while elimination works toward reducing the concentration. Early on, the amount of drug absorbed per minute is more rapid than the amount eliminated per minute – which is why the concentration rises during this period. As more and more of the drug is absorbed from the GI tract (and less and less remains in the GI tract to be absorbed), the amount of drug being absorbed per minute slows down. At some point, the rate of drug coming into the body equals the rate at which it is being eliminated. It is at this moment in time that the maximal concentration is achieved. As the rate of entry of drug into the body becomes less than the rate of elimination, the concentration of drug in the body begins to decline. Eventually, the total dose of the drug is absorbed and the elimination of drug from the body governs the changes in the concentration versus time curve. Thus, if we increase the rate of absorption, without changing the rate of elimination, the time at which the peak concentration occurs will be sooner. If you’d prefer to think of it quantitatively, the following equation is useful:

 

t_max = [ln(k_a/k)]/(k_a – k)

 

where k_a is the first-order rate constant for absorption and k is the first order rate constant for elimination. Since the two constants are in both the numerator and denominator, most of us don’t find just looking at the equation particularly helpful in determining whether t_max will increase or decrease with a given change in the absorption rate. The equation can be helpful in several other ways. First, it makes it quite clear that the time to the maximal concentration is a function of the absorption rate and the elimination rate. Second, it provides a means for us to simulate what happens to t_max when you change one rate constant and keep the other the same.

 

 

Last revised 06/04/04

 

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

 

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