L6 Quantitative Pharmacokinetics Flashcards
Fu equation gives
The fraction of drug unbound in plasma
The plasma concentration-time curve - what info does it give us
- dose
- frequency of drug administration
- toxicity
Routes of administration
Intravenous and oral
Therapeutic window
a concentration range bounded at the lower end by the minimum concentration that produces the desired clinical effect and at the upper end, the concentration that produces unacceptable effects or where no further benefit is observed.
In a plasma concentration-time curve what is C(max), T(max) and AUC
- Cmax - peak plasma concentration
- Tmax - the time required to achieve Cmax
- area under the curve
minimum toxic concentration (MTC)
the upper limit of the therapeutic window. Drug concentrations above the MTC increase the risk of undesired effects
Minimum effective concentration (MEC)
the plasma drug level below which therapeutic effects will not occur
First- and zero-order kinetics
First- and zero-order kinetics refers to changes in the amount of drug in the body as a function of time
First-order kinetics [def]
change by a constant fraction per unit time
Zero order kinetics [def]
Change by a constant amount per unit time
First-order kinetic
elimination of most drugs follows first order kinetics
- clearance and half-life are constant
- constant fraction of drug is eliminated per unit time
- can change from first order to zero order as the drug concentration increases and elimination mechanisms become saturated
The larger the margin inbetween the MTC and MEC is better or worse for drugs
better
Zero-order kinetics
- drugs are removed at a constant rate which is independent of plasma concentration
- elimination of a few drugs (e.g., alcohol*ethanol bc of al) follows zero-order kinetics
- all the active sites on an enzyme or transporter are occupied - saturated elimination mechanisms
Plasma-conc graph I.V and oral drug conc starts where
I.V - 1
Oral - 0
Drug clearance
Drug clearance refers to the efficiency of drug elimination, defined as the ratio of the elimination rate (e.g., mg∙h-1 ) to the concentration of drug in plasma (e.g., mg∙L-1 )
total body clearance =
total body clearance = hepatic clearance + renal clearance + clearance by other routes
[clearance by a specific organ]; renal clearance =
renal clearance = glomerular filtration + active secretion - reabsorption
fe
- the fraction of administered drug
excreted unchanged in the urine
What clearance if low fe
hepatic clearance bc metabolites excreted
What clearance if high fe
Renal clearance bc parent drug is excreted
Drug bioavailability
Drug bioavailability (F) is the fraction of administered dose of the parent drug that reaches the systemic
circulation
First order kinetic graphs [1IV]
plasma-time = curved graph
- also be straight if natural/inverse log
Zero order kinetic graph [1IV]
Straight graph
Enzyme of ethanol
Alcohol Dehydrogenase
is Alcohol Dehydrogenase easily saturated
yes
Drug bioavailability must be given in
fraction or percentage
bioavailability of an orally administered drug
* obtain plasma concentration-time curve of the drug via ____ and ___routes
i.v. and oral
Determine total body clearance in NCA
a simple approach to determine (Cltotal) in NCA
- administer a single dose of drug (i.v. bolus or oral)
- collect blood samples and measure drug plasma concentration at defined time points
- plot a plasma concentration-time curve, and calculate the AUC
Compartmental (requires___) or non-compartmental analysis (___)
modelling
NCA
Use the___ method to calculate AUC
trapezoidal
elimination rate constant (k)
the slope of the ln[plasma concentration]-time curve for drugs that follow
first-order kinetics - indicates the fraction of a drug removed per unit time
- CL(total) / -V(d)
drug elimination half-life (t1/2)
the time taken for the drug plasma concentration to decrease by 50% and is calculated during the elimination phase
- CL(total) and -V(d)
steady-state concentration [def]
steady-state concentration is the concentration of drug in the plasma reached when the rate of drug absorption is equal to the rate of drug elimination following repeated or continuous dosing
How to get higher steady-state concentration
higher doses and/or more frequent dosing will result in higher steady-state concentrations
steady-state concentration-to achieve clinical response rapidly:
loading dose (=
Vd × target plasma-concentration) followed by
maintenance dose
drug elimination half-life (t1/2) is proportional to ___ and inverse proportional to __
- V(d)
- CL(total)
increased Vd, e.g., in pregnancy [and]
decreased Cltotal, e.g., liver/kidney disease lead to what
an increase in drug elimination half life.
