2.3: Metabolism

2.3 Overview of Metabolism

The next pharmacokinetic phase is metabolism. Drug metabolism or biotransformation is the chemical alteration or breakdown of the drug’s structure. Although most drug metabolism occurs in the liver, the enzymes responsible for metabolizing drugs and other foreign substances (xenobiotics) are found in most tissues within the body.

As mentioned above, most biotransformation reactions take place in the liver. These biotransformation reactions are categorized into two phases: Phase I and Phase II. Phase I reactions introduce or uncover a functional group on the drug molecule, which makes it more amenable to phase II metabolism. Phase II metabolism then makes the drug molecule more water soluble to allow its free extraction from the body in the urine.

2.3.1 Phase I reactions

Phase I reactions work by modifying drug molecules through an interaction with enzymes in the liver. The primary Phase I metabolizing enzymes are in the Cytochrome P450 enzyme family, which has many subtypes. Once the metabolic pathway for a medication is known (i.e., the metabolizing subtype of Cytochrome P450 has been identified), clinicians can understand and better manage how a medication may interact with other medications, food, and herbal supplements the individual is taking. Such interactions are the underlying mechanisms for many unintended medication outcomes and may influence enzyme activity by inhibition or induction.

2.3.2. Induction and Inhibition

Enzyme Inhibition Drug Interactions:

Often, when patients take multiple medications that undergo Phase I metabolism, there can be competition for the active site of a P450 enzyme, which can reduce the rate of metabolism and lead to the accumulation of one or both enzyme substrates. This process is known as competitive inhibition. Another type of enzyme inhibition is called non-competitive enzyme inhibition. In contrast to competitive inhibition, non-competitive inhibition does not involve direct competition for a finite number of active sites on the enzyme for metabolism. Instead, it occurs when one medication causes a conformational change to an enzyme structure after binding to a separate site of the enzyme. Panel A of Figure 2.3.2 shows the standard binding of substrate to an enzyme. Panels B and C illustrate competitive and non-competitive enzyme inhibition. Panel 2B/C demonstrates the effect of adding an inhibitor (either competitive or non-competitive) on the blood concentration of an enzyme substrate.

Enzyme Induction Drug Interactions:

In enzyme induction drug interactions, one medication increases the transcription of an enzyme responsible for the metabolism of another drug. When this occurs, the rate of drug metabolism can be increased, reducing the plasma concentration and effectiveness of the medication. Enzyme induction processes and their effect on plasma concentration of the enzyme substrate (other medication) are depicted in Figure 2.3.1, Panels A and D, respectively. Of note, the effect of enzyme induction on the substrate concentration may be gradual or delayed, as it takes time for the increased transcription of new enzymes to occur.

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Figure 2.3.2: Enzyme Induction Drug Interactions. (CC-BY 4.0; Riley Cutler and Delilah Przybyla)

2.3.3 Phase II Reactions

In Phase II metabolism, various enzymes catalyze the conjugation of endogenous molecules to the enzyme substrate drug. These reactions include glucuronidation, acetylation, or sulfation. The metabolite of this phase of metabolism is transformed into a more water-soluble molecule that is more readily excreted from the body.

2.3.4 Saturability of Metabolic Processes

The body's ability to metabolize medications depends on the availability of the metabolizing enzymes. If the drug's concentration exceeds the availability of the metabolizing enzymes, the metabolic process is said to be saturated. When enzymatic saturation is reached, patients can be at high risk for adverse effects as drug concentrations may rise rapidly with additional intake, and the half-life can be exceedingly prolonged as the elimination of the drug is significantly compromised.

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This section titled Metabolism is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Karen Vuckovic from Introduction to Pharmacology by Carl Rosow, David Standaert, & Gary Strichartz (MIT OpenCourseWare) via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request. Figures by Riley Cutler.