Clinical Chem Therapeutic Drug Monitoring

Learning Outcome

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