PK (ADME) principles Flashcards
drug movement route (absorption)
drug enters gut > gut wall for intestinal absorption (some drugs are metabolised here)
> enters the circulation > portal vein > liver (liver metabolises or excretes it via biliary excretion)
> eventually the site of absorption (systemic absorption)
methods for drug metabolism after absorption
LIVER and INTESTINAL MUCOSA
1) phase 1 reactions: oxidation, reduction, hydrolysis
2) phase 2 reactions: conjugation with polar endogenous compounds (to increase water solubility)
methods for drug excretion (route)
1) kidneys (renal)
2) biliary tract (high MW drugs, conjugate metabolites)
3) sometimes lungs for volatile agents
drug concentration formulas
concentration
amount (A)
volume of (V)
C = A / V
C (drug in plasma) = A (plasma) / V (plasma)
C(unbound) = Au / V blood
f(unbound) = C (unbound) / C
what are examples of disease states that can affect f(unbound)?
renal disease
hepatic disease
surgery
severe burns
surgery
pregnancy
what is the systemic bioavailability equation
F = F (F) . F(G) . F(H)
F = feces
G = gut
H = hepatic
breakdown of body water volume in 70kg human
plasma water 4% (3L)
whole blood vol 8% (6L)
extracellular water 20% (14-15L)
- consists of extravascular (interstitial space) and intravascular (plasma)
total body water (including intracellular) 60% (42L)
what is the equation for (apparent or initial) volume of distribution?
V (L) = dose (mg) / C(0) concentration (mg/L)
relates to
amount of drug in body to the concentration of drug in the plasma
= this includes binding to tissues (fat, muscles), proteins, plasma, etc.
to find the apparent volume of distribution , use conc = C(0), upon entry into the systemic circulation, and before the drug is metabolised and excreted
what are the plasma proteins that bind drugs? and the characteristics of drug-plasma protein binding?
albumin
a1 glycoprotein
lipoproteins
transcontin
drug-lipoprotein association is relatively weak
- acidic drugs bind exclusively to albumin
- basic drugs bind selectively to a1 glycoprotein but may also bind to albumin and lipoproteins
what are the characteristics of drug-tissue binding?
acidic drugs tend to have small V due to high affinity for plasma albumin and low affinity to tissue proteins
basic drugs tend to have large V due to extensive tissue binding (even though affinity for plasma and tissue is comparable)
what are the equations for clearance
CL = rate of elimination (mg/min) / concentration of drug (mg/ml)
= ml/min
related to extraction ratio
CL = Q (blood flow) x E (extraction ratio)
- extraction ratio has no units
CL (total in blood) is the sum of CL of individual components.
what is extraction ratio and what is the formula
E is the fraction of drug removed from the blood or plasma as it crosses the eliminating organ
E = C (A , arterial) - C (V, venous) / C (A, arterial)
what are the parameters that affect bioavailability?
1) Physicochemical properties of the drug or dosage form
- size, lipophilicity, charge, solubility
2) Route of administration
3) Lability of drug to pH and enzymes
4) Membrane barriers
- membrane porosity
- membrane thickness
- involvement of transporters
effects of high E
and
the drug characteristics related to it
if E is very high, i.e., close to 1 (>0.7),
CL = Q . E = Q (1)
then the clearance is limited by blood flow
drug has high efficiency in:
1) Partitioning out of blood cells
2) Dissociation from plasma proteins
3) Permeation through hepatic
membranes
4) Metabolism by hepatic enzymes
5) Biliary excretion into bile
what is intrinsic clearance
intrinsic clearance refers to the elimination of drug via metabolism in the hepatocyte
dependent on hepatocellular enzymes
effects of low E
and
the drug characteristics related to it
if E is very low (<0.3)
CL Q . E
then the clearance is limited by capacity
- sensitive to changes in plasma protein binding or hepatocellular eliminating activity (e.g., interference from another drug)
the drug likely,
1) is a poor substrate for the elimination
process
2) is polar and has insufficient lipophilicity to permeate readily into hepatocytes
3) is substrate of efflux transporter along
the sinusoidal (basolateral) membran
importance of E and how it is affected by different diseases?
E is important predictor of a drugs binding, the blood flow, and intrinsic clearance of a drug
certain diseases
1) kidney disease
- decrease în glomerular filtration rate
2) liver disease
- decrease in hepatic enzymes
- CIRRHOSIS = decrease in blood flow
both combined = may decrease the albumin levels (increase leakage in kidney disease, decrease product in liver disease)
will decrease the clearance of drug
enterohepatic cycling
A process where drug is secreted into bile, stored in and released from the
gallbladder, transit into the small intestine, and reabsorbed there back into circulation
renal clearance equation
Rate of excretion
= (1 - F(R)) x (rate of filtration + rate of secretion)
if divide by concentration
CL(e) = [1-F(R)] x [CL(f) + CL(s)]
where F(R) is the fraction reabsorbed
rate of filtration refers to glomerular filtration
rate of secretion refers to tubular secretion (from capillaries to tubules)
ONLY water soluble drugs / metabolites made more soluble AND are also UNBOUND are filtered via GFR
- protein bound drug is too large to
pass through fenestration of glomerulus
how is CL(f) = f(u) x GFR obtained (the equation) and the implications
rate of filtration = GFR x C(u)
divided by C
CL(f) = GFR x f(u)
if drug is only filtered and not secreted,
then CL(R) = CL(f) = GFR x f(u)
if CL(R) > GFR x f(u), then there is likely active secretion of the drug.
what are the other factors that affect the absorption of a drug through the GIT? (in terms of physiological)
1) total absorptive area
- intestines have larger surface area
2) blood flow through the intestinal capillaries
3) permeability of membrane
- intestines > stomach
4) drug metabolising enzyme
- enterocytes in the intestines
what are the other factors that affect the absorption of a drug through the GIT? (in terms of physiochemical) (in solution)
1) size
gut permeability decreases with >500 MW
2) log P
more lipophilic = better permeability
3) charge
charged moves slower across the membrane
factors affecting drug absorption in SC and IM vs GIT (in solution)
the factors affecting GIT do not apply for SC and IM absorption
- due to the porosity of the capillaries, small molecules (drug) will rapidly enter the systemic circulation (F almost = 1)
dependent on
physiochem
- solubility of drug
physiological
- blood flow (increased with heat, fever, exercise, decreased with vasoconstriction, systemic shock)
- vascularity (IM>SC)
what are the other factors that affect the absorption of a drug through the GIT? (in terms of physiochemical) (in solid dosage form) + explanation
include conditions where this may be affected
1) gastric emptying rate
2) intestinal motility
factors affecting
- food (volume, degree of fluidity, type)
- drugs (opioids(slowdown), pro kinetic agents)
- physiological state (vomiting, pregnancy, body position).
explanation
- rate of presentation of drug
- regardless of whether dissolution»_space; absorption (or vice versa), slow down in motility will allow for (i) more time for absorption, (ii) more time for complete dissolution
all other physiological and physiochemical factors remain the same
how does changing disposition kinetics (change in CL and V) affect PK parameters (cmax, tmax, t1/2, AUC) in extravascular dosing?
CL decrease:
will cause k to decrease (H1) = increase in rate of elimination will be slower
1) cmax will increase
2) tmax will increase (longer time for rate of absorption to match rate of elimination)
3) AUC increase (J6)
4) t1/2 increase (H2)
V decrease:
will cause k to increase (H1) = increase in rate of elimination will be faster
1) cmax will increase
2) tmax will decrease
3) AUC same
4) t1/2 decrease (H2)
components of equation C4
Ka = association constant
f(up) = fraction of unoccupied binding sites
P(T) = total protein concentration
P = total concentration of unoccupied protein.
what is the relevance of C4 and how do different physiologic states affect it?
1) alterations of P(T) due to
- decreased hepatic biosynthesis of albumin in uremia and cirrhosis
- induction of a1 glycoprotein in uremias, inflammatory disease, cancers
2) alterations to P
drug drug interaction
3) alterations to Ka
- genetic variants of albumin and a1 glycoprotein
- disease induced medication of a1 glycoprotein
what are the factors affecting Q(H), f(u), CL(int)
Q(H),
- exercise, hydration, posture, drug, disease (cirrhosis)
f(u),
- disease (cirrhosis, uremias), genetic variation, drug interaction causing displacement.
CL(int) = refers to hepatocellular eliminating activity
- disease (cirrhosis, uremias), genetic variation, drug interaction causing transporter/enzyme inhibition
how does equation F4 change in different extraction ratios and its impact on C(u) and oral admin
LOW EXTRACTION (E)
F4 becomes CLb,H = f ub x CL int
- sensitive to changes in protein binding.
when fub is increased due to displacement
- Cu remains relatively unchanged and not clinically significant (no need for dose adjustment)
HIGH EXTRACTION (E)
F4 becomes CLb,H = QH
- insensitvie to changes
when fub is increased due to displacement
= Cu increases = potentially clinically significant
HOWEVER, in oral dose,
there is the effect of E
F = 1 - E
in this case, high E drugs will have a more significant change in F, and based on the equation J6, there will be a significant change in AUC and C total
= will require dose adjustment for initial and maintenance doses.
effect of urine flow on CL(R)
CLR increases as urine flow increases for drugs that are mostly reabsorbed
(less time for reabsorption)
effect of urine pH on CL(R)
CLR of non-polar acidic and basic drugs are sensitive to urine pH changes
CLR of polar acidic and basic drugs are independent of urine pH changes
- polar = cannot cross tubular membrane layer.
