Lec3-5 Flashcards
lipophilicity
solubility in lipid relative to water
lipophilicity is measured by
oil/water partition coefficient (drug conc in oil v water)
drugs with carboxylate reside undergo ionization and become ____
what is their solubility to water and lipid now
anions
more soluble to water
less soluble to lipid
drugs with amine undergo ionization and become ____
what is their solubility to water and lipid now
cation
less soluble to water
more soluble to lipid
quaternary ammonium with fixed positive charge (such as ACH) has what type of lipophilicity
lipophilicity is low
high solubility in water
low solubility in lipid plasma membranes
very large MW drugs
> 1000 (tend to be proteins)
small MW drugs
<1000
pharmacokinetics is concerned with
the time course of
- absorption
- distribution
- eliminiation
absorption
drug from site of administration into the blood stream
why is conc of plasma important
bc it’s what we can measure (blood)
distribution
from blood stream into tissues in body
elimination
getting out of body in form of molc it was administered
4 major types of biotransport
passive diffusion throguh plasma membrane
filtration
carrier-mediated transport
receptor-mediated endocytosis
what order kinetics is passive diffusion and is the half life or rate dependendant on dose conc
first order
half life NOT dependent on conc
rate IS dep on conc gradient
transport in bulk flow of aqueous fluid is known as
filtration
filtration rate is dependent on ? (3)
hydrostatic pressure
MW, size, charge
tissue porosity
what type of transport can be active transport of a molc that wouldn’t cros w/o it
carrier-mediated transport
drug transporter whose efflux pump causes resistance to some antitumor drugs
MDR p-glycoproteins
biotransporter that is important for big molecules
receptor-mediated endocytosis
rate of receptor mediated endocytosis is dependent on
receptor expression and membrane insertion
what protein therapeutics is receptor-mediated endocytosis a mechanism for
monoclonal antibodies (iGg)
time course of transport from site of administration to systemic circulation
absorption
bioavailability is the
% dose absorbed (what % gets into bloodstream)
only route of admin that’s 100% bioavailabity
intravenous bc all put into vasculature
route of admin with fastest possible input rate
intravenous
during subcutanrous or intramuscular routes of admin where do low MW lipophilic drugs enter
where do high MW compounds enter
low - into blood
high - into lymphatics
subcutaneous and intramuscular has better biovailability than ____ for ____ drugs
than oral route
for polar & high MW drugs
during inhalation route of admin, rapid absorption of gases and vapors is due to
high pulmonary blood flow
low diffusional distance from alveolus to blood
which route of admin do we want no bioavailability
inhalation
why is absorption through skin (topical route) generally slow
moves through surface layers of dead, keratinized cells
which route avoids the first pass effect
topical (i.e. transdermal)
why might bioavailabity of oral route be low
mucosa as barrier high MW low lipophilicity carrier-mediated extrusion first pass effect
biotransformation during the absorption process
first pass effect
is bioavailability low or high in a drug with NO first pass effect
high bioavailability
time course of transport from vasculature to tissue space
distribution
what determines equilibration rate during distribution
blood flow
highly perfused organs?
intermed?
low?
high: lung liver brain kidney
inter:
skeletal muscle
low:
fat
which is equilibrated faster? highly perfused structures or low
highly bc equilibrate in mins while low does in hours
determinants of equilibrium gradient in distribution
vascular permability
macromolc binding in plasma and tissue
MW, lipophilicity, carrier affinity
BBB has what 2 things that allow drugs to pass
tight junctions and transporters
what does a drug binding to albumin do & whats its effect on equilibrium gradient
it prevents the complex from moving out of the vascular compt
as drug distributed, dissociated from albumin and incr drug distribution (high equilibrium gradient)
monoclonal antibody likely to distribute into a space like that of
albumin (in plasma)
volume of the body into which the drug appears to have distributed once equilibrium is obtained
volume of distribution
(plasma) concentration is
amount (g) / volume (L)
volume of distribution is determinant of
plasma concentration
one compt model v 2
1 compt - drug ditributes entire volume and reaches equilibrium v quickly
2 compt - equilibrates slowly
high lipid solubility means ____ Vd
high
high MW(proteins) - ___ Vd
small MW and polar(charge) - ____ Vd
small MW and lipophilic - _____ Vd
highly lipophilic and accumulates in fat - ____ Vd
small (Vd about plasma vol, 4%)
Vd like sucrose (Vd about extracell fluid vol, 17%)
Vd like water (Vd about total BW, 58%)
more than body water (»58%)
mechanism by excretion or biotransformation
elimination
molc in same chemical configuration as the form it was injected in is by
excretion
clearance is what over what
volume of plasma cleared over unit time
what is the extraction ratio & what is it’s range of values
Cp arterial - Cp venous
0=nothings removed
1=all of drug is removed
what determines the elimination rate of a drug from the body
total clearance
elimination rate (amt of drug in body/time) =
Cl Total x Cp
where Cp=plasma conc
elimination rate changes in parallel w
plasma conc
total clearance = sum of
renal and nonrenal clearance
renal clearance refers to
nonrenal
urinary excretion unchanged
all other routes and mechanisms
nonrenal clearance participates in biotransformation where critical enzymes are lumped into phase 1 and phase 2
-whats the general difference
1- oxidation, reduction, hydrolysis
2-conjugations
pathway of biotransformation
drug –phase 1 –> metabolite –phase 2–> conjugated metabolite
main enzyme for phase 1
CYP450
2 isozymes of CYP450
3A4 and 2D6
how do CYP450 familu isozymes differ
substrate specificity
inducers
inhibitors
what happens to clearance of some drugs when theres biotransfortmation w an inducer
increases clearance
what are good ligands for phase 2 conjugation
OH
good ligands for phase 1
CH3
phase 2 conjugating MOieties (6)
GMS GAG glucoronic acid methyl groups sulfate glutathione acetyl group glycine
phase 2 enzymes that are transferase creater metabolites with ___ compared to parent
higher MW
volume of plasma cleared by excretion unchanged into urine
renal clearance
mechanisms of renal clearance
Glomerular filtration of unbound low MW drug
prox tube secretion mediated by oatp and mdr
passive reabsorption of uncharged, lipophilic drug
why is renal clearance small
bc readily reabsorbed
equation for renal clearance
urinary excretion rate / Cp
Cp=plasma conc
if renal clearance is 0-120 (
not filtered and/or lots of reabsorption or bound to macromolc in plasma
if renal clearance is 120 (GFR) it’s mechanism of excretion was
filtration and NO reabsorption
if renal clearance is 120-640 (RPF) it’s mechanism of excretion was
filtration and secretion
NO net reabsorption
*>GFR only happens if secreted into nephron in prox tubule and no net reabsorption
renal clearance is most likely what for:
high albumin binding
<120
renal clearance is most likely what for:
lipophilic drug
<120
filtered but reabsorbed
renal clearance is most likely what for:
acidic drug w affinitiy for OATP, high urine pH
> 120
OATP means likely to be secreted so incr ClR
if drug is anion (wk acid) then it’s more charged in high pH –> less reabsorption –> incr ClR
renal clearance is most likely what for:
acidic drug w low urine pH
<120
would want a more basic pH if drug is acidic
what type of distribution? drug rapidly equilibrates into volume of distribution
single compartment distribution
type of elimination?
drug is cleared at constant fractional rate
Kel (elimination constant) is fraction eliminated per unit time
first order elimination
does total clearance depend on dose
no
how do you linearize plasma conc
take ln
bioavailability with iv
100%
compute vol of distribution
dose/Cp0
elimination half life is function of both
Vd and clearance
tiem to eliminate 50% of a drug from plasma
half life
is half life dose depend or independ? what order of elimination?
dose independent
first order
if you incr Vd what happens to half life
larger Vd –> lower Cp0 –> (longer or) incr half life
increase clearance what happens to half life
faster clearance (higher ClT) so shorter half life * no effect on CP0
how are Cp, Vd, ClT, and half life affected with dose
Cp incr w dose
rest do not change
with iv admin, 1st order elimination, 1 compt distribution, rapid reversible effect, and no active metabolits
if you double dose, what happens to duration
duration increases by addition of one half life
what type of elimination has Cp v time as linear without log transformation
zero order
in zero order kinetics, how does biotransformation time change w conc
50% biotransformation time incr w conc
main diff bn first ortder and zero order Cp v time
first order has fractional elimination like it decr by half
zero order has constant rate of elimination like decr by 20 every hour
is eliminiation happening from the central or peripheral compt? what are central organs? peripheral?
central
central: lung liver kidney brain
peripheral: fat and skeletal muscle
Cp v time curve for two compt model has 2 phases, what are they and what do they describe
alpha - initial rapid decline that describes distribution of drug from central in peripheral comp
beta - linear
which most similarly acts/looks like the plasma conc v time curve of a 2 compt model? highly perfused or poorly perfused tissue concentration
highly perfused tissue (central compt like brain)
what happens to conc of poorly perfused tissue as Cp decreases
they rise/ incr til reach equilibirum
duration of action for multi-compartments is dependent on
distribution into and out of compt where target is located
what do lipophilic drugs that act in the brain duration of action depend on
redistribution out of brain to slowly perfused tissues
**not on elim by kidney or liver
can duration of action be short if elimination half life is long
yes
half life is always elimination
false theres an absorption half life
plasma conc time curve is influenced by what 3 things
absorption rate constant
elimination rate constant
bioavailability
the faster the absorption (i.e. the shorter the half life of absorption), the ___ Cp max and the ____ t max
higher Cp max
earlier the tmax (so the time for that peak is shorter)
fraction of dose that gets into plasma conc is known as
bioavailability
what is proportional to bioavailability
area under the curve of Cp v t
integral of Cp = AUC = ?
Fx D / ClT
bioavailability x dose / total clearance
*ClT is constant
the absolute bioavailability is determined for
a new drug
the relative bioavailability is determined for
generic in comparison to proprietary formulation of drug
*comparing one manufacturers formualtion to anoteher
eq for absolute bioavailability and relative
abs: AUC nonIV dose / AUC IV dose
rel: AUC formualtion 1/AUC formualtion 2
during continuous infusion, at steady state what 2 rates equal each other
input rate = output rate
input rate =
Cp steady state * ClT
*also true for output rate equation
equation that relates Cpss w infusion rate
Cpss=infusion rate / ClT
the higher the ClT the ____ the Cpss
lower the Cpss
*unless you increase the infusion rate to get a desired CPss
tiem to achieve steady state level achieved by infusion depends SOLELY on
elimination half life
time to reach 50% of Cpss take how many elimination half life
one
time to reach 93% of Cpss take how many elimination half life
four
when prescribe a drug by continuous IV infusion, which drug will reach steady state mor quickly? shorter half life or longer
shorter half life
Cmin is called a
trough
CmaxSS to CminSS is
therapeutic window
when is loading dose important
for rapid onset of effect is needed
if drug elimination half life is LONG and slowly attains SS
diff bn multiple dose kinetics and IV infusion
multiple is not continuous, it’s pulsatile
equation for multiple dose kinetics
maintenance dose / dosing interval
extent of accu,ulation from first dose to SS depends on
ration bn elimination half life and dosing interval
if dosing interval is 7 times the elimination half life, how much accumulation?
none
if dosing interval = elimination half life, how much accumulation?
2 fold accumulation
calculate Cp average
input rate / clearance
(D/t) / Cl T
compare the Cp avg of small dose at frequent intervals and high dose at long intevals
they’re about the same
