Clinical Chem Therapeutic Drug Monitoring

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%

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

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

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

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

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