1st Pass vs. 2nd Pass Metabolism

First-pass and second-pass metabolism refer to the stages of drug metabolism in the body. This process is crucial for therapeutic ketamine administration, affecting the drug’s bioavailability, efficacy, and potential side effects.

  1. First-Pass Metabolism: This refers to the initial phase of drug metabolism that occurs after oral administration. When taken orally, ketamine is first absorbed by the mucal membranes. The mucus membranes are the body’s primary site of oral, nasal, and RDT metabolism. During first-pass metabolism, the drug enters the systemic circulation directly. This process can significantly increase the amount of drug that reaches the systemic circulation, thereby increasing its bioavailability. In the case of ketamine, second-pass metabolism transforms it into norketamine, a less potent metabolite.
  2. Second-Pass Metabolism: refers to the subsequent phase of drug metabolism after the drug has entered the stomach and passed to the liver. During second-pass metabolism, the drug circulates throughout the body and undergoes further metabolism in the liver or other tissues. This process can further reduce the number of active drugs in the body and can lead to the formation of additional metabolites. In the case of ketamine, second-pass metabolism can lead to the formation of additional metabolites, such as hydroxynorketamine, which are thought to contribute to the feeling of being hungover after dosing.

For therapeutic ketamine administration, these metabolic processes are important considerations. Ketamine is often administered via non-oral routes (such as intravenous or intranasal) to encourage more first-pass metabolism and increase its bioavailability. This allows for a more potent and rapid onset of effects. However, second-pass metabolism still occurs and can contribute to the drug’s effects and potential side effects.

It’s also worth noting that individual differences in liver function and metabolic enzymes can influence the rate and extent of first-pass and second-pass metabolism, leading to variability in responses to ketamine therapy. Therefore, individualized dosing and careful monitoring are often necessary for therapeutic ketamine administration.

Here are four sources that provide information on first-pass vs. second-pass metabolism for therapeutic ketamine administration purposes:

  1. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy
  2. Ketamine for Treatment-Resistant Unipolar Depression
  3. Ketamine: Synthesis, metabolism, and pharmacodynamics
  4. Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide

Please note that while these sources provide information on the metabolism of ketamine, they may not specifically distinguish between first-pass and second-pass metabolism. First-pass vs. second-pass metabolism is a more general term and not specific to ketamine. More generally, it refers to the idea that some drugs are extensively metabolized by the liver (first pass) before they reach systemic circulation, which can greatly affect the bioavailability of the drug. Second-pass metabolism refers to the further metabolism of substances already distributed throughout the body.

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