Podgorski - ADME Flashcards
Predominant mech of membrane crossing:
Driving force:
passive diffusion
conc. gradient
Other means by which drugs cross membranes (4)
aq channels in the intercellular junctions
lipid cell membranes
active pumps or co-transpoters
cellular endocytosis/exocytosis
Larger lipid solubility =
Larger lipid solubility = Greater ability to cross membranes.
Access to cells, cellular organelles, nervous system
Henderson-Hasselbalch Equation
pH = pKa + log (unprotonated/protonated)
Where does acid accumulate?
basic compartments. Aspirin goes from stomach to plasma
Acids vs. Bases protonation
A- = HA B = HB+
Body fluids with potential for drug “trapping”
Urine (pH 5-8) Breast Milk (6.4-7.2) Jejenum, ileum (7.5-8) Stomach (1.9-2.6) Prostate secretions (6.45-7.42) Vaginal secretion (3.4-4.2)
Ampicilin is a weak organic acid with a pKa of 2.5. What percentage of a given dose will be in a lipid soluble form in the duodenum at pH of 4.5?
about 1%
How does first pass metabolism affect the bioavailability of propranolol?
propranolol – 73% of oral dose
destroyed by first pass metabolism
Bioavailability def:
Percent or fraction of the orally administered dose that actually enters systemic circulation
Vd=
Vd=(amount administered)/(concentration at t=0)
or otherwise written
Vd = Dose/Plasma Drug Conc.at t=0
-t=0 is found via extrapolation
How do you determine the volume of distribution? (4 steps)
- Administer known amount of drug i.v.
- Take blood samples at various times and
measure drug concentrations. - “Plot log concentration as a function of time.
- Extrapolate straight line through linear data
points back to time = 0 to estimate blood
concentration when amount in body is known
and before any loss due to elimination
occurs.
significance of Vd
Vd is the apparent volume of plasma that would have yielded the extrapolated conc. at t=0 upon administration of the dose. It relates the amount of drug in the body to the conc. in blood or plasma
Early vs. late time points
Early time points- plasma concentration depends on distribution out of the plasma and elimination process from the body
Later time points – controlled by elimination only (straight line)
What property of the drug determines Vd?
lipid solubility: high lipid solubility = low plasma concentration = large Vd
binding to plasma protein: high binding = trapping of drug in the blood = small Vd
Range of Vd values in a 70kg person:
5 -10 liters – drugs highly charged or bound to plasma protein
20-40 - moderately lipid soluble
40 - lipid soluble enough to distribute to the total body of water
> 40 - high lipid soluble; sequestered in fat, nervous tissue, and muscle
Can some highly lipid soluble drugs have Vd <40?
Note: some highly lipid soluble drugs are bound to plasma proteins and, as a result, have Vd values of less than 40 liters
Consequences of high lipid solubility
Access to liver cells and
accumulation in the ER where
cytochrome P450 enzymes responsible
for hepatic metabolism are located.
Access to CNS. Tight junctions in the
capillary endothelium and lipoidal glial
cells provide a barrier against entry of
compounds into the brain.
How are CNS drugs eliminated?
hepatic metabolism
Effect of plasma protein binding on elimination of drugs
How is there a possibility of drug-drug interaction?
Drug action correlates with free drug
concentration rather than total plasma drug
Slower elimination because bound drug is not
filtered in the kidney and not metabolized in
the liver
Possibility of drug-drug interaction if a second
drug is administered that competes for plasma
protein binding (Example – WARFARIN and
other oral anticoagulants can displace some
drugs causing temporary rise in their free
drug concentration).
Elimination types:
rule of thumb:
Urinary, liver, combo
RULE OF THUMB: drugs can be directly eliminated if they’re hydrophilic (polar)
Urinary excretion (3)
Renal glomerular filtration
Tubular secretion (active)
Passive reabsorption
Renal glomerular filtration
Unbound drugs only -
‐ Changes in glomerular filtration rate affect the rate of elimination of drugs, (e.g., digoxin, kanamycin).
Tubular secretion (active)
Probenecid
- transport against concentration gradient -
‐ drug/metabolite selectivity -
‐ probenecid and secretion of penicillins
Probenecid: competitively inhibits the tubular secretions of the penicillins, prolongs the duration of the effect of penicillins
Passive reabsorption
enhanced lipid solubility favors reabsorption -
‐ pH -
‐ rate of renal flow
nonionized, lipid-solubule drugs are extensively reabsorbed into plasma, while ionized and polar molecules will remain in the renal filtrate and are excreted via urine.
What does intravenous sodium bicarb do?
alkanlinizes urine to pH 8
How do you acidify urine?
administer ammonium chloride. Changes pH to 5.
Biliary excretion
works for high molecular weight or glucuronidated drugs
enterohepatic cycling (results in prolonged presence of drug or toxin
cholestyramine – as approach to interrupt enterohepatic cycling
Ezetimibe
Reduced intestinal absorption of cholesterol -
‐ t1/2 in the body > 20 hrs -
‐ Benefit: lower LDL cholesterol
Choroid plexus
Choroid plexus: active secretion of compounds from cerebral spinal fluid into the blood
