E1 L9: Bioavailability and Clearance 4: Flashcards
When fe is 0
Hepatic clearance is the same as renal clearance
What directional changes in AUCiv and CL are expected
Decrease clearance, and increased AUCiv
What directional changes in AUCpo and F are expected?
Decrease intrinsic decreased oral
Increased oral AUC
Q: Assuming 100% oral absorption, co-administration of an enzyme inducer with a low EH drug (Drug X) would:
A. Significantly increase F of drug X
B. Significantly decrease F of drug X
C. Significantly increase CLH of drug X
D. Significantly decrease CLH of drug X
C. Significantly increase CLH of drug X
Q: Assuming 100% oral absorption, co-administration of an enzyme inducer with a high EH drug (Drug Y) would:
A. Significantly increase F of drug Y
B. Significantly decrease F of Drug Y C. Significantly increase CLH of Drug Y
D. Significantly decrease CLH of Drug Y
B -significantly in decrease F of drug Y
Q: Assuming 100% oral absorption and fe = 0, co-administration of an enzyme inducer with a high EH drug (Drug Y) would:
A. Significantly increase Cl of Drug Y
B. Significantly increase CLpo of Drug Y
C. Significantly increase F of Drug Y
D. Significantly increase AUCiv of Drug Y
B. Significantly increase CLpo of Drug Y
Some drugs are eliminated unchanged in the urine. We can determine how much of a drug is excreted unchanged into the urine by collecting and analyzing urine concentration data
Renal excretion
Approx. - of cardiac output goes to the kidneys; of the volume - is filtered in the glomerulus; this is the Glomerular filtration rate (GFR) (120ml/min)
20%; 10%
Only (bound/unbound) drug is filtered
Unbound
Over 90% of the filtered volume is reabsorbed in the
Renal tubules
Filtration occurs in the
Glomerulus
Filtration depends on
Molecular weight
and unbound drug concentration in plasma (fu)
Filtration equation
CLR = Fu * GFR
Secretion equation
CLR > fu * GFR
Reabsorption equation
CLR < fu * GFR
Drug A PK parameters are as follows:
CL: 500 ml/min
fu: 0.95
fe: 1
Q: T/F:
1. Hepatic metabolism is a major elimination pathway
2. T/F; Significant reabsorption occurs
False - Hepatic is not major, it is minor (Fe = 1)
False - when you compare clearance (fe is 1, means clearance is the same as renal clearance)
Occurs in proximal tubule
Secretion
T/F: secretion is an active carrier mediated process
True
Saturable; there are separate transporters for acids and bases from plasma into urine. In general, neutral drugs are not secreted
If rate of excretion > rate of filtration, then infer that
secretion has occurred.
Are good substrates for renal transporters and dissociate rapidly from plasma proteins so as not to limit secretion. Amount of secretion is dependent only on renal blood flow e.g. para-amino hippuric acid (ER ~1)
High renal excretion drugs (High ER)
Are poor substrates for renal transporters; even through blood sits at the proximal tubule for ~30 seconds, transportation is the limiting step. Amount of secretion depends on unbound concentration of drug in blood and is independent of renal blood flow
Low renal excretion drugs (low ER)
Secretion may depend on:
Plasma protein binding (fu)
Kidney blood flow
Drugs actively secreted by the kidney: Acids
Penicillin’s
Probenecid
-Share same transporters cam compete with each other situation
T/F: Passive process for exogenous products including drugs
True
If rate of excretion < rate of filtration
Infer that reabsorption has occurred
If CLR < fu * GFR, then
reabsorption has occurred (secretion may have occurred, but reabsorption is greater)
Factors affecting renal reabsorption of drugs: properties of drugs and physiological factors:
Properties:
Polarity
Ionization
Physiological factors:
Urine flow
Urine pH
Polar compounds (are/are not) best absorbed
Are not
Ionized compounds (are/are not) best absorbed
Are not
High plasma protein binding (increases/decreases) drug excretion
Decreases
Faster urine flow (increases/decreases) drug excretion
Increases
Urine pH can vary widely from
4.5 to 7.5 (average 6.3)
Variations of Urine pH are due to forced
acidification/alkalization
Respiratory or metabolic acidosis/alaklosis and drugs
Urine pH is mostly important for
nonpolar drugs that are weak acids (salicylates) or weak bases (amphetamine)
Acidification of urine (decreased pH) promotes reabsorption of
weak acids and promotes CLR of weak bases
Alkalization of urine (increased pH) promotes reabsorption of
Weak bases and promotes CLR of weak acid
(Phenobarbital is a weak acid its renal elim is governed by reabsorption)
Q:
1. T/F: Pheno is more ionized in basic urine pH
2. Pheno’s renal absorption is less in basic urine pH
3. Pheno’s CLR would decrease upon urine alkanization
- True
- True - more drug ionized, less reabsorption
- False
Q: For a patient with a phenobarbital I(aspirin) overdose, what drug can increase CLr most significantly
Acetazolamide (alkalize)
T/F: Methamphetamine is more ionized in acidic urine vs basic
True
T/F: Methamphetamines renal absorption is more acidic in urine pH
False
T/F: Methamphetamine’s CLR would increase upon acidification
True
Drug that is polar in its unionized form is not reabsorbed
Strong acids (pKa<3) and strong bases (PKa>12) are completely ionized over urine pH range, therefore undergo little reabsorption
Very weak acids (pka > 8) and very weak bases (pKa<6) will be unionized in the urinary pH range and will be reabsorbed in this range, resulting in low CLR and insensitive to pH, e.g. phenytoin (acid) propoxyphone (base)
Situations insensitive to urinary pH
(Effects of urine pH on CLR)
GFR is influenced by
Filtration
Urine flow rate is influenced by
Reabsorption
Urine pH is influenced by
Reabsorption
Renal transporters are influenced by
Secretion
