Pharmacokinetics II Flashcards
What is the purpose of metabolism (biotransformation)?
- decrease lipid solubility (i.e., make a drug more water soluble)
- increase ionization
What event is caused by biotransformation?
increased body excretion
What are three mechanisms/purposes of biotransformation?
- lipophilic –> hydrophilic
- active drug –> metabolite
(metabolites can act as an active drug, active toxicant, or be inactive) - pro-drug –> active drug
How does metabolism occur?
Phase I
- reactions include oxidation (CYP 450), reduction, deamination, and hydrolysis
Phase II
- reactions that involve addition (i.e., conjugation) of subgroups to -OH, -NH2, and -SH functional groups on a drug molecule
What is biotransformation?
- process by which chemicals (drugs) are modified by the organism
- usually occurs by enzymatic reaction
- present for endogenous as well as exogenous substrates (vitamins, steroids, hormones, drugs, etc.)
What are three mechanisms of metabolism (alteration of drug)?
- lipophilic to hydrophilic
- first pass effect (oral administration)
- cytochrome P450
Why is biotransformation necessary?
If no biotransformation, drugs/substances will stay in body for much longer; biotransformation can eliminate them from the body in hours
How does the first-pass effect, and subsequent liver passes, affect a drug?
the drug passes through the liver several times, more and more gets metabolized and eventually eliminated
What is path of blood circulation (first-pass)?
Oral administration –> GI Tract –> absorbed into portal vein –> Liver –> Hepatic Vein –> heart –> aorta:
–>hepatic artery –> liver –>….
or
–> i) celiac artery; ii) superior & inferior mesenteric arteries –> GI Tract –>….
What is the importance of biotransformation?
- a key determinate of therapeutic half-life
- may produce “active metabolite”
- site of “drug-drug interaction” (drugs can increase half life of another drug/increase metabolism, inhibit other drugs, etc.)
- produces toxic metabolites for intermediates
What are the results of biotransformation?
- stops pharmacological effect (of parent drug); with the exception of production of an active metabolite
- restricts distribution (remains in plasma, filtered by kidney)
- facilitates excretion
What are the key organs involved in biotransformation - high capacity?
liver
What are the key organs involved in biotransformation - medium capacity?
intestine, lung, kidneys
What are the key organs involved in biotransformation - low capacity?
skin, testis, placenta, adrenals
*not that significant relative to liver
Is the brain involved in biotransformation?
functional activity of enzymes for metabolism in brain is not clear right now - don’t know much
Biotransformation can make a drug more hydrophilic, what is the result of this?
because it becomes hydrophilic, it does not cross biologic membranes very well, so stays in kidney and is excreted in the urine
