PHARMACOKINETICS AND BIOPHARMACEUTICS (46:138)

LECTURE TUTORIAL

Effect of Route of Administration on Xenobiotic Disposition and Action

 

Key Terms:

 

Enteral: Within the intestine. Technically, only those routes wherein drug is ultimately absorbed from the intestine represent enteral routes of administration (such as oral and rectal). However, the term enteral is commonly used to refer to any route of administration that involves absorption anywhere from the mouth to the rectum. Thus, sublingual administration is often categorized as an enteral route of administration.

 

Postprandial: Occurring after a meal. The term in an example in the lecture referred to the rise in blood glucose that occurs after a meal.

 

Percutaneous: Absorption through unbroken skin (as opposed to placement on a mucous membrane).

 

Topical: relating to a definite place of locality. Used for drug administered at the site at which it will be absorbed (e.g., skin, nasal mucosa, eye).

 

  

Key Principles:

 

First-pass effect: This is an extremely important phenomenon to understand. Whenever the route of administration is such that there is an organ of elimination between the administration site and the systemic circulation, there is the potential for a first-pass effect. This is sometimes referred to as presystemic elimination. The consequence of the first-pass effect is that the fraction of drug reaching the systemic circulation is substantially reduced. This explains, for example, why the dose of propranolol that is administered intravenously is so much less than that administered orally. After oral administration, all of the drug must pass through the liver before reaching the systemic circulation. This results in exposure to drug metabolizing enzymes prior to the drug reaching the systemic circulation. The intestinal wall can also represent a site of first-pass metabolism. In later lectures, we will discuss the factors that influence the first-pass metabolism of drugs.

 

Precipitation of drug at the site of administration can have a marked effect on the blood concentration versus time profile. This is most commonly seen after intramuscular administration, but can also occur following other parenteral routes (e.g., subcutaneous). Numerous drugs on the market today are poorly soluble in water. As such, parenteral preparations of these compounds contain co-solvents to solubilize the drug. But once the preparation is injected into the muscle, the diluent is diluted by the fluid in the muscle, the composition of the fluid in which the drug is dissolved thus changes, resulting in drug precipitating out at the site of injection. In order for absorption to take place, drug must redissolve which is a slow process. As a consequence, administration of some drugs by the intramuscular route results in a slow release of drug from the site. If the dose administered is large enough, this can function as a sustained release preparation. However, if normal doses are given, the rise in drug concentration may be slowed to the degree that drug never achieves concentrations above the minimally effective concentration. Thus, while the duration of drug in the body may be longer than that seen with an aqueous drug, the duration of action may be substantially less after similar doses.

 

Practice Problems:

 

1.        For a small lipophilic drug administered orally in solution form, the rate-limiting step for absorption is gastric-emptying. True or False? Explain your answer. Answer

 

2.      UI138 is administered in the form of radioactive drug. After both oral and intravenous administration, 98% of the radioactivity of the administered dose is recovered in the urine. In contrast, the area under the curve for parent (unchanged) drug after intravenous administration is 8 times that seen after oral administration. Does UI138 undergo significant first-pass metabolism after oral administration? Provide a justification for your conclusion. Answer

 

3.        Intramuscularly administered drug will always exhibit a faster onset of action than the same dose of drug administered orally. True or False? Answer

 

4.     Drugs administered by the intravenous route are always 100% bioavailable. True or False? Explain your answer.  Answer

 

5.     Quick dissolving tablets, such as seen with many over-the-counter preparations (e.g., benadryl and imodium) are designed to provide buccal absorption of the drug.  True or false?  Answer

 

6.    Name two enteral and two topical routes of administration that avoid the first pass effect.  Answer

 

 

  Last revised 07/17/04

 

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

 

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