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

• 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

• 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