Drug Absorption and Distribution/MRT Flashcards
What is ADME
Pathway of drug administration
Pathway of drug absorption
What is bioavailability (F) and what is Absorption rate constant (ka, kabs)
F: Proportion of extra-vascular dose that is absorbed intact to systemic circulation
Ka, Kabs: Rate of drug absorption from extravascular dose
CL, V and k must be the same in each individual, regardless of dosage form
Why is the apparent values for CL and V higher than the true values when drugs are given by vascular routes (e.g. oral, rectal and intramuscular)
CL = D/AUC
- When CL is calculated, D is the dose that was given to the patient (e.g. 50 mg), but the amount of drug reaching the systemic circulation (plasma) is less than 50 mg
- The AUC is true data, but the ‘available’ dose is less than the nominal dose given to the patient.
What is apparent CL and apparent V?
What is the bioavailability (F) formula calculated from the AUC of the extra-vascular dose (e.g. oral, rectal, IM), compared to the AUC of the IV dose
How to calculate Ka (absorption rate constant)
What is the first pass (absorption principles)? Discuss first pass loss
For some drugs, systemic absorption after oral administration depends on both enzymatic metabolism and efflux transporters in the intestinal epithelium. The presence of efflux transporters on the apical side in concert with the intracellular metabolism may diminish the movement of drug from the intestinal lumen to blood. Inhibition of either metabolic activity or the efflux transport leads to an increase in the net movement of unchanged drug into systemic circulation
Liver metabolism: loss of drug during the ‘first pass’ through the liver is the conventional (traditional) definition of ‘first pass loss’’
Intestinal (gut wall) metabolism: intestinal metabolism may be regarded as a component of overall ‘first pass loss’
What is rate limitation (absorption principles)?
Compare one-compartment (body) model and two-compartment (body) model
Provide a graph of a two-compartment model
How to calculate of A, B, α and β (IV data)
Provide an example of drug distribution in muscle, liver, fat and plasma
How does plasma and tissue binding happen in the tissue and central compartment?
Discuss plasma protein binding and what drugs are involved
Albumin
- MW ≈ 65,000
- Plasma conc. ≈ 35-50 g/L
- Reduced in liver disease, renal failure and pregnancy
- Drug binding to weak acids (anions), NSAIDs (naproxen, ibuprofen), penicillins, phenytoin, warfarin
Alpha1-acid glycoprotein
- MW ≈ 44,000
- Plasma conc. ≈ 0.4-1.0 g/L
- Increased in stress/trauma, infection, inflammation and renal failure
- Drug binding to weak bases (cations), propranolol, lignocaine, quinine
> Fraction (of drug concentration) unbound in plasma [fu]
> Highly bound drugs have fu < 0.1 ( More than 90% bound to proteins)
fu = Cu / C (plasma concentration unbound / plasma concentration total)
- Free drug concentration is ‘active’ and fu may increase in conditions where low serum albumin occurs
- Drug interactions (displacement of drugs from protein binding sites can increase fu)
Volume of distribution equation (when volume is increased)
Volume of distribution equation (when volume is decreased)
What is mean residence time (MRT)
- average time of residence of all molecules in the dose (of the drug)
- time for 63.2% of the dose to be eliminated (∴ independent of t½)
- ratio of AUMC (moment curve) : AUC
- model-independent parameter
Equation and formulas for MRT
Compare MRT with IV and Oral
IV Dose
AUC = 569 mcg.h/L
AUMC = 2993 mcg.h2/L
T1/2 = 3.6 hour
MRT = 5.3 hr
Oral Dose
AUC = AUC = 568 mcg.h/L
AUMC=3199 mcg.h2/L;
MRTOral = 5.63 h
MAT = 0.37 h
What is the MRT concept
MRT(IV) = 1/k
V = CL/k
V = CL × MRT
As MRT is model-independent, volume of distribution is “Vss”
MRT calculations for one-compartment model
MRT calculations of two compartment model
MRT calculations for IV data
Give en example of how to calculate V, V1 and Vz from a graph
How to calculate V1 ?
How to calculate Vz
(volume of distribution during the terminal phase)
How to calculate Vss
Volume of distribution during steady state
Provide a summary of V1, Vz and Vss
