B2.070 Pharmacokinetics: Relationships Among Dose, Exposure, and Effects Flashcards
therapeutic index
difference between therapeutic and toxic ranges
pharmacodynamics
effects of the administered drug
desired = efficacy
undesired = toxicity
pharmacokinetics
getting the drug to the right place in the right amount
components of pharmacokinetics
absorption
distribution
metabolism
excretion
absorption
how a drug gains entry into systemic circulation
passive diffusion
direct passage through lipid bilayers of cell membrane
driven by concentration gradient
most common way for drugs to cross cell membranes
smaller, less polar molecules
carrier mediated transport
transporters facilitate movement
structural selectivity
competition by similar molecules
saturable
facilitated diffusion
a type of carrier mediated transport
facilitates passage of polar or charged molecules
does NOT require energy
moves DOWN gradient
active transport
energy dependent carrier mediated transport
transport coupled to ATP hydrolysis (primary) or co transport substrate down a gradient (secondary)
can move AGAINST gradient
most rapid
important sites of active transport
enterocytes hepatocytes neuronal membranes renal tubular cells blood brain barrier
absorption of APAP
passive diffusion
max plasma concentrations at 0.5-1 hr
F = 0.7-0.9
blood
very large molecules
highly charged molecules
extracellular water
large
very polar
water soluble
total body water
smaller
water soluble
*acetaminophen
adipose tissue
lipid soluble
bone and teeth
ions
chelators
other tissues
specific uptake mechanisms or binding proteins lead to drug accumulation
apparent volume of distribution
the compartment where a drug appears to distribute
C0
extrapolated concentration of drug in plasma at time 0 after equilibration
Vd
amount of drug/C0
list in order of smallest to largest Vd: ECF, total body water, plasma water, tissue conc
plasma
ECF
total body water
tissue concentration
what factors influence distributions
gender
age
body fat
edema
what does Vd really represent?
relative distribution between plasma and the rest of the body
Amt = Vd * C0
Amt = (VpCp)+(VaCa)+(Vb*Cb)
what does a large Vd indicate?
high drug concentrations in one or more tissues
why is Vd qualitatively important in clinical use?
indicates ration of plasma concentrations to concentrations in tissues
why is Vd quantitatively important in clinical use?
allows calculations of total amount of drug in body
supports dose determination to achieve a target concentration
key determinant of half life
*more useful than qualitative
primary parameters
clearance and Vd
inherent properties
clearance
primary parameter for elimination (metabolism + excretion)
secondary parameters
half life
elimination rate constant
Kel
CL/Vd
t0.5
0.693*Vd/CL
amt of drug in body at any time
Vd*plasma concentration
APAP Vd
0.7 L/kg
total body water
metabolism (biotransformation)
many drugs are hydrophobic, but efficient excretion requires water solubility
metabolism increases water solubility and excretion
phase 1 metabolism
introduce/unmask a functional group
relatively few atoms involved
oxidation, reduction, or hydrolysis
phase 2 metabolism
synthetic reactions
addition of molecules
require specific functional groups
do drugs always undergo both phase 1 & 2 metabolism?
no, can do either, both, or neither
what are 2 different outcomes of phase 1 metabolism?
- drug metabolite w modified activity produced
2. inactive drug metabolite produced
types of phase 2 metabolism
water soluble: -glucuronidation -sulfate conjugation -glycine conjugation lipid soluble: -acetylation -methylation detoxification: -glutathione conjugation
dominant phase 1 metabolic enzymes
CYP family (cytochrome p450) high activities in enterocytes and liver contribute to first-pass effect
dominant phase 2 metabolic enzymes
UGTs
SULTs
NATs
what are the 3 metabolic pathways of APAP
sulfation catalyzed by SULTs
glucuronidation catalyzed by UGTs
oxidation catalyzed by CYP2E1 + conjugation of oxidation product catalyzed by GSTs
what transporters are involved in APAP metabolism
no transporters for APAP
no transporters for glutathione conjugate and metabolites of glutathione conjugate
ATP driven active transport for secretion of glucuronide and sulfate conjugates from hepatocyte into bile or blood
excretion
how xenobiotics or their metabolites are eliminated from the body
amount excreted by any process per unit time is proportional to…
rate of elimination for that process
concentration of drug in plasma
drug concentration in plasma is inversely proportional to….
volume of distribution
- larger volumes eliminated slower
- lower volumes eliminated faster
renal excretion
generally smaller MW
favored by high aqueous solubility
excretion by active and passive processes
hepatic/biliary excretion
generally larger MW
less polar environment
excretion by active and passive processes
excretion of APAP
APAP excreted in urine
glutathione conjugate is metabolized and excreted in urine
glucuronide and sulfate conjugates mostly excreted in urine, with lesser amount in feces
elimination rate (mg/hr)
CL (L/hr) * C (mg/L)
what is one way to think about clearance?
all drug being taken out of a set amount of plasma in a set amount of time
-volume of plasma cleared of drug per unit time
total body clearance…
sum of hepatic and renal clearance
first order kinetics
absorption rate= kabs[drug] distribution rate=kdis [drug] metabolism rate=kmet [drug] excretion rate=kexc [drug] -parameters proportional to concentration of drug
zero order kinetics
elimination rate = k
no proportionality, constant over all concentrations
rate limiting part of first order kinetics
drug concentrations
how do drug concentrations change in first order kinetics?
by some constant fraction per unit time
half life of first order kinetics
constant (independent of dose)
dose-independent pharmacokinetics
log plasma conc. vs. time is straight line
catalyzed or facilitated processes are….
saturable
at low concentrations or a catalyzed/facilitated process
first order kinetics rates proportional to dose Vd constant clearance constant half life constant
at saturating drug concentrations of a catalyzed/facilitated process
zero order kinetics rates are constant regardless of dose Vd may vary clearance may vary half life varies
