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