Clinical Chem Therapeutic Drug Monitoring

Learning Outcome

• To understand the clinical importance of drug monitoring
• To outline the possible analytical issues in therapeutic drug monitoring

Therapeutic Drug Monitoring

Considerations:

• route of administration
• rate of absorption
• drug distribution within the body
• rate of elimination

Routes of administration

• a drug must be at an appropriate concentration at its site of action
  • maximum therapeutic benefit
• bioavailability - the fraction of initial administered dose of the drug that reaches its intended site of action or the systemic circulation
• different routes of drug administration
  • different characteristics that affect the circulating drug concentrations
• intravenous → most direct and effects + bioavailability is 100%
• others: intramuscular, subcutaneous, transcutaneous oral administration; inhalation; rectal delivery
  • bioavailability is generally lower than 100%

Rate of absorption

• drug absorption - transportation of the unmetabolised drug from the site of administration to the body circulatory system

• mechanisms of drug absorption:

  • passive diffusion
  • carrier-mediated membrane transport
  • nonspecific drug transporters

• gastrointestinal drug absorption

  • dependent on:
  • dissociation of the drug from its administered form
  • solubility of the drug in gastrointestinal fluid
  • its diffusion across the gastrointestinal membrane
  • tablets/capsules or %%liquid form%%?
  • weak acids or weak bases?
  • passive diffusion or active transport?

• net movement of a drug from gastrointestinal lumen into systemic circulation

• mainly by passive diffusion at gastrointestinal epithelium

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• {{in stomach:{{

  • orally administered drug must encounter the low pH in gastric juice and digestive enzymes
  • thick mucous layer and short transit time
  • limit drug absorption
  • determine drug formulation

• {{in intestines:{{

  • overcome numerous digestive enzymes
  • largest surface area for absorption
  • membranes are more permeable
  • influenced by gastric emptying time, microflora in the intestinal tract and intestinal transit time
  • most drugs are absorbed in a predictable manner among healthy people
  • absorbance rate can be altered by
  • changes in intestinal motility
  • pH
  • inflammation
  • coadministration of certain foods or drugs
  • age, pregnancy or other pathologic conditions

Drug distribution

• transfer of the unmetabolised drug from one location in the body to another after absorption
• drug dynamics - only free or unbound fraction interacts with its site of action & produces biologic responses
• free fraction of circulating drug diffuses out of the vasculature into interstitial and intracellular spaces
  • relative proportion of drug between circulation and tissues
• protein binding is influenced by:
  • protein concentration
  • pH
  • metabolic abnormalities
  • presence of other chemicals
• drug distribution is impacted by:
  • blood perfusion
  • blood & tissue binding proteins
  • regional pH
  • permeability of cell membranes
  • body water composition
  • fat composition
  • diseases

Rate of elimination

• drug elimination - irreversible removal of an administered drug from the body, or from the plasma/blood, via either
  • excretion of the unmetabolized drug in its intact form through renal, biliary, pulmonary, salivary or milk excretion
  • metabolism followed by excretion
• hydrophilic drugs - directly excreted by kidneys
• hydrophobic drugs - metabolic biotransformation before excretion
• metabolism - mainly in liver
• excretion - mainly in kidneys
• significant dysfunction → accumulation of the drug or its metabolites in toxic concentrations

hepatic drug biotransformation - 2 metabolic pathways

• Phase I

  • oxidation, reduction & hydrolysis
  • catalysed by ^^hepatic microsomal enzymes^^
  • cytochrome P450
  • CY3A4 responsible >50% of existing drugs
  • various classes: opioids, immunosuppressants, antihistamines, benzodiazepines

• Phase II

  • covalent binding of polar group to non-polar drug molecules → ^^become water-soluble^^
  • allow renal or biliary excretion
  • polar adjuncts: amino acids, glucuronic acid, glutathione, acetate & sulfate
  • example: glucuronidation pathway catalysed by UDP-glucuronosyltransferase enzyme

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• renal excretion

  • free fraction of the drugs or its metabolites is filtered in the kidneys, and excreted in the urine
  • drug elimination rate directly relates to glomerular filtration rate

• biliary excretion

  • liver actively secretes ionised drugs into bile to be:
  • eliminated in faeces; or
  • reabsorbed as part of the enterohepatic cycle

Pharmacokinetics

• activity of a drug in the body as influenced by absorption (A), distribution (D), metabolism (M), and excretion (E) of the drug
• study of the disposition of a drug after its delivery to an organism
• how the body interacts with administered drugs for the entire duration of exposure
• half-life - amount of time for serum drug concentrations to decrease by 50%
• most drugs are delivered on a scheduled basis (e.g., once every 8 hours)
  • blood drug concentrations oscillate between the peak drug concentration (maximum) and trough drug concentration (minimum)
  • multiple-dosage regimen
  • 5-7 doses are required before reaching a steady-state

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