Drug-Drug Interactions and Biotransformation

Drug-Drug Interactions - Biotransformation

• Drug interactions can occur when medications compete for the same enzymatic pathways.
• Complications from drug interactions may not become evident until later stages of treatment.
• Most problematic combinations involve two specific drugs.

Warfarin Clearance and Coagulation

• Cimetidine has an inhibitory effect on the clearance of warfarin, affecting coagulation time.

Drug-Drug Interactions Overview

• The risk for interactions increases with polypharmacy (the use of multiple drugs).
• The Physician's Desk Reference (PDR) provides information on drug interactions, focusing on CYP isozyme involvement.
• Drug inserts contain similar information to the PDR.
• Reports of adverse drug interactions typically follow complications.
• Several drugs have been withdrawn from the market due to harmful interactions.

Preventing Drug-Drug Interactions

• Patients should be profiled for their biotransformation capacity using phenotyping strategies and a combination of markers, although this ideal approach is challenging.
• Screening drugs for specific CYP isozymes can help predict interactions by grouping drugs according to their metabolic pathways.
• Drug interaction tables offer valuable insights into potential drug interactions and the involved CYP isoforms.

Dietary Effects on Biotransformation

• Citrus juices, particularly grapefruit juice, can significantly alter the pharmacological activity of certain medications.
• Grapefruit juice is notably effective at increasing the half-life of multiple drugs, including:
  • Immunosuppressants like Cyclosporine A
  • Benzodiazepines like Midazolam
  • H1-antihistamines like Terfenadine
• Grapefruit juice inhibits CYP3A isozymes, affecting drug metabolism and necessary dosing frequencies.

Biotransformation Process

• Biotransformation modifies chemicals, such as drugs, through enzymatic activity present in the body.
• This process is essential for both endogenous substances (like hormones) and exogenous compounds (like drugs).

Purpose of Biotransformation

• The main goal is to reduce lipid solubility, thus increasing water solubility and ionization for better excretion.

Pharmacological Effect and Drug Concentration

• Therapeutic effects of drugs correlate with plasma concentration until a maximal effect is achieved; higher concentrations beyond this point do not enhance efficacy.
• CYP3A is notably affected by grapefruit juice, specifically the compound bergamottin, which inhibits its activity.

First Pass Biotransformation

• Oral drugs undergo first pass metabolism in the gastrointestinal tract and liver, resulting in less drug reaching systemic circulation.
• This necessitates larger doses and presents individual variability in drug metabolism.

Human Variation in Biotransformation

• Biotransformation capacity shows reasonable consistency, but significant variation (up to threefold or more) can occur due to genetic factors, sex, and age.

Age-Related Changes

• Drug metabolism can be underdeveloped at birth but reaches adult levels within 1–3 months.
• Aging tends to increase the half-life of drugs, such as diazepam, affecting pharmacotherapeutic outcomes.

Impact of Liver Disease

• Liver disease can significantly impair biotransformation processes, emphasizing the importance of liver function in drug metabolism.

Acetaminophen Biotransformation

• The majority of acetaminophen doses are excreted through metabolic pathways, which must be closely monitored to prevent toxicity.
• Understanding liver morphology is crucial for evaluating the risk of acetaminophen hepatotoxicity.

Acetaminophen Toxicity

• Acetaminophen overdose can lead to severe liver damage, highlighting the need for awareness of its biotransformation and potential adverse effects.