PHARMACOKINETICS AND BIOPHARMACEUTICS (46:138)

LECTURE TUTORIAL

Routes of Elimination of Xenobiotics

 

Key Terms:

 

Biotransformation: The chemical modification of xenobiotics after administration, generally catalyzed by enzymes.

 

Enterohepatic Recycling: Numerous drugs undergo elimination via the bile in the unchanged or conjugated form. Drugs eliminated in the bile are available for absorption in the GI tract. This re-entry into the body after ‘elimination’ via the bile results in the “recycling” of drug and prolongs the time required for the drug to be irreversibly eliminated from the body.

 

Cholephil: An agent whose bile:plasma ratio is >1. Such agents are actively secreted into the bile.

 

Half-life: The time required to reduce the amount of drug in the body or concentration of drug in blood by 50%.

 

Clearance: A quantitative measure of the rate of drug elimination from the body divided by the concentration. This term will be discussed in much greater detail in future lectures, as it is arguably the most useful pharmacokinetic parameter.

 

Steady-state: The point at which the rate of input of drug into the body is equal to the rate of elimination. As such, the amount or concentration in the body reaches a plateau.

 

Key Principles:

 

Understanding the route of xenobiotic elimination is important in making drug selection and dosing decisions in patients with disease: Where possible, one would like to avoid a drug whose elimination is largely dependent upon an organ with compromised function (e.g., avoid drugs primarily metabolized in patients with liver disease). If a patient has renal failure and normal liver function, it would be preferable to select an agent that was eliminated completely by the liver and did not depend upon renal elimination at all. However, it should be recognized that most hepatic elimination occurs via metabolism. The metabolites formed are generally more polar than the parent compound. As a consequence, even drugs that are ‘eliminated’ solely by hepatic metabolism often depend on renal excretion for ultimate elimination of the xenobiotic (in the form of metabolite) from the body. Numerous studies have demonstrated that metabolites may accumulate to substantial levels in the presence of renal disease. Most drugs are eliminated by multiple pathways. This may become important in determining the quantitative impact of disease in an organ of elimination for a particular drug (i.e., How much does renal disease alter the elimination of drug X?).

 

Molecular weight and polarity are the primary determinants of biliary excretion: Agents that are excreted in the bile are generally large polar molecules. This would include many drugs conjugated with glucuronic acid. Some drugs have been specifically designed so as to increase the fraction of the drug that is eliminated in the bile. This provides some options when needed to treat patients with significant renal dysfunction. Selecting a drug eliminated primarily by biliary excretion obviates the need to make dosage adjustments due to the patients reduced renal function.

 

Enterohepatic recirculation can lead to an increase in the half-life of drugs: Drugs secreted into the bile enter into the gall bladder, which is periodically emptied into the small intestine. Drug that enters the small intestine in this fashion may be absorbed back into the body. Obviously, some fraction of what is absorbed will be secreted into the bile again, while the rest will enter the systemic circulation. As a consequence, drug that is ‘eliminated’ from the systemic circulation via biliary secretion may re-enter the body. This prolongs the length of time that a drug is in the body. If this cycle is interrupted, such as through the oral administration of an agent that binds the drug and prevents its absorption from the intestine (e.g., activated charcoal), the half-life of the drug will decrease. It is important to recognize that glucuronide metabolites may be deconjugated in the intestines, resulting in the availability of parent drug for reabsorption. The intestinal microflora contain an enzyme that can cleave glucuronide conjugates. Thus, though the glucuronide metabolite is not reabsorbed to a significant extent, when such metabolites are eliminated in the bile enterohepatic recirculation may take place if deconjugation occurs. Chloramphenicol would be a good example of a drug that goes through this route.

 

Elimination via a route that is quantitatively small may be clinically significant: For example, compared to the amount of drug eliminated by the liver or kidney, very little drug is eliminated via the hair. Yet elimination via hair may be a very useful means to assess drug exposure, especially drugs of abuse. This represents a non-invasive method that can provide information on drug exposure long after drug is at concentrations below the limit of detection in blood or urine. Tears would be another example of a quantitatively minor pathway of elimination, but one that may be useful in the determination of drug concentrations as a guide to therapy.

 

Half-life is a useful parameter for the determination of time-dependent variables in drug administration: Drugs administered chronically are often given in a regimen designed to achieve a target concentration associated with the desired effects. But how long does drug have to be administered to see the maximal benefit that will be achieved with a given regimen? This is often determined by the time that it takes to reach the plateau concentration (Though sometimes the drug acts through indirect mechanisms and the time to maximal effect is a function of the pharmacodynamics of the drug and not pharmacokinetics. A good example would be the delayed effect of tricyclic antidepressants in the treatment of depression.). The time to reach steady-state is determined by the half-life. When using drug concentration as a guide to drug therapy, we most commonly want to wait until the patient has achieved a steady-state concentration before obtaining a blood sample for drug concentration determination.

 

Drug metabolism is the single most important source of variability in drug response: While many factors contribute to variability in drug response (see slide 10 for this lecture), none makes as large an impact as variability in drug metabolism. The impact of variation in drug metabolism is especially important for drugs that exhibit an extensive first-pass metabolism after oral administration. Indeed, the most significant drug interactions are generally caused by alterations in drug metabolism. For this reason, it is very important that students understand the pathways and factors governing drug metabolism.

           

Practice Problems:

 

1.         Graph the relationship between molecular weight and % of drug excreted in the bile. Answer

  

2.         Drugs that undergo enterohepatic recirculation sometimes demonstrate an interesting phenomenon seen in the plasma concentration versus time curve. After oral administration, concentration will rise to achieve a peak (as expected), then begin to decline (which is expected after the absorption phase is complete). However, during then decline phase, there are episodic periods of increases in the drug concentration (without the administration of additional doses of drug) that provides a declining curve interspersed with multiple ‘blips’ of brief increases in concentration. This phenomenon is most readily seen with drugs that have a long half-life. Provide an explanation of this phenomenon in the context of biliary excretion.  Answer 

 

3.        Drug X has a half life of 4 hours and is administered as an intravenous bolus dose to produce a concentration of 100 mcg/ml. How long after administration of the dose of Drug X will the concentration drop to 25 mcg/ml? Answer

 

4.        Theophylline is administered to a patient as a constant intravenous infusion at a rate of 25 mg/hr. After 3 days of the infusion, the steady-state concentration is found to be 10 mg/L. What is the clearance of theophylline in this patient?  Answer

 

 

 

  Last revised 07/17/04

 

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

 

Return to the Index for Lecture Tutorials

 

Return to Pharmacokinetics and Biopharmaceutics Homepage