Drug Elimination

Drug Elimination

Drug elimination begins immediately after administration.  Elimination is achieved through metabolism and excretion.

Hepatic Metabolism

The kidneys are unable to significantly excrete lipophilic drugs.  The drugs must be transformed to a more polarized form to be eliminated by the kidneys.  The liver is the primary site of metabolism.

Phase I Metabolism

• Adds or uncovers a polar functional group such as an amine group.

• Alcohol dehydrogenase and amine oxidation are other examples of Phase I Metabolism.

• The Cytochrome P450 system is part of Phase I Metabolism.

Phase II Metabolism

• Drugs requiring additional polarization undergo further metabolism.

• Glucuronidation is an example of Phase II Metabolism.

Cytochrome P450 System

The cytochrome P450 system (CYP450) is a group of enzymes in the liver and GI tract that metabolize a wide variety of drugs and naturally occurring compounds such as hormones and lipids.  The enzymes exist in many forms and specialize in metabolizing certain compounds:

• CYP3C9/10

• CYP2D6

• CYP3A4/5

Polymorphisms in CYP450 enzymes lead to variability in patient response to drugs. For example, clopidogrel (an antiplatelet drug with cardiovascular indications) is converted to an active form by CYP2C19. Some individuals' CYP2C19 is not effective at metabolizing clopidogrel, which makes the drug ineffective.  

CYP450 can be induced and inhibited.  

• Induction of CYP450 can increase metabolism of drugs and make the drugs ineffective at the usual dose. For example, St. John's Wort induces CYP3A4 and reduces the effectiveness of drugs metabolized by CYP3A4.

• Inhibition (competitive and non-competitive) of CYP450 reduces the metabolism of some drugs, which results in increased therapeutic effect and possibility of toxicity.  For example, ketoconazole (an antifungal medication) inhibits CYP3A4, which is the isozyme that metabolizes warfarin (a blood thinner). Concomitant use of ketoconazole and warfarin can lead to dangerous bleeding tendencies if warfarin dosing is not adjusted.

 

Renal Elimination

Most drugs and compounds are eliminated through the kidneys.  Poor kidney function may lead to accumulation of drugs and toxicity.  As noted above, drugs are metabolized into forms that are able to be excreted by the kidneys.  

Path 1 - Drugs are filtered through Bowman's capsule into the renal tubules.

Path 2 - Weak acids and bases are actively excreted into the tubules.

Reabsorption - Reabsorption in the distal tubule can occur by diffusion across a concentration gradient.  Ion trapping can be used to limit this process.  By alkalinizing the urine, weak acids can be trapped in the renal tubule. Similarly, by acidifying the urine, weak bases can be trapped in the renal tubule.  This concept can be used therapeutically to enhance elimination of unwanted drugs/metabolites.