Bioavailability and Clearance Review Flashcards
(87 cards)
1
Q
What are determinants of bioavailibility for oral doses?
A
- Intestinal absorption
- Intestinal metabolism (insignificant for most drugs)
- Hepatic metabolism
2
Q
Do most drug molecules have significant intestinal metabolism?
A
No; Most drugs have shown insignificant intestinal metabolism. Thus, low bioavailibility is usually due to poor intestinal absorption and high hepatic metabolism during the first pass through the liver.
3
Q
What is the first-pass effect?
A
Significant loss of drug during the first pass through the liver after oral administration
* If you have a drug that is significantly metabolized by the liver during a single pass (ex. 90% of the drug is metabolized every time the drug goes through the liver)
* Oral–> assuming 100% intestinal absorption
* IV–> the liver recieves 25% of cardiac output
4
Q
What are the two major elimination pathways?
A
- Hepatic Metabolism
- Renal Excretion
5
Q
CLtotal=
A
CLh + CLr
Hepatic CL + Renal CL
6
Q
What limits the maximum clearance?
A
The maximum possible clearance for the whole body is limited by cardiac output (CO) because the heart determines how much blood is delivered to eliminating organs (liver, kidney, lungs, etc.).
- Therefore, maxium CL values are cardiac output
7
Q
What is the maximum organ clearance?
A
- Each organ has a maximum possible clearance limited by its blood flow.
- Maximum organ clearance = blood flow to that organ
8
Q
How are most drugs eliminated?
A
- metabolism to polar metabolites and the metabolites are excreted into the urine.
- Some drugs are eliminated unchanged in the urine.
9
Q
What does fe stand for?
A
- fraction of dose excreted unchanged into the urine
10
Q
fe=
A
Total drug excreted unchanged/dose
OR
CLr/CL
11
Q
CLr=
A
CL x fe
12
Q
CLh=
A
CL-CLr
13
Q
What is CLb?
A
Blood Clearance
* Reminder: most drug molecules are found in the plasma (protein bound or free)
14
Q
How do we differentiate between plasma concentration vs blood concentration?
A
- Most drugs distribute into the plasma.
- Certain drugs such as tacrolimus and cyclosporine bind to RBC significantly. For these drugs, drug concentrations are typically measured using blood (not plasma) samples. (blood/plasma >15)
- If all drug molecules are distributed in the plasma, then drug conc. in plasma= drug amt in the blood. (Cb/Cp= 0.5-0.6)
15
Q
What is the systematic clearance and how does it relate to the drug conc. in the plasma?
A
- systemic (plasma) clearance= CL
- The proportionality constant relating the rate of drug elimination and the drug concentration in plasma.
dA/dt= -CL(Cp)
Cp= plasma concentration
16
Q
What is the blood clearance?
A
- CLb
- The proportionality constant relating the rate of drug elimination and the drug concentration in the blood.
- dA/dt= -CLb(Cb)
17
Q
How can the CLb be estimated from CL and blood/plasma ratio?
A
Rate of drug elimination from blood = rate of drug elimination from plasma
* CLb = CL (Cp/Cb)
* OR …CLb= CL/(Cb/Cp)
For drugs mainly distributed into the plasma Cb/Cp= 0.5
* SO, CLb= 2(CL)
18
Q
How do we interpret AUCblood and AUCplasma if Cb/Cp= 0.5?
A
- CLb= Doseiv/AUCiv
- AUCiv- estimate from the blood vs time profile
For Cb/Cp= 0.5,
* AUCblood= 1/2(AUC plasma)
* ONLY if the drug is mainly distributed in the plasma
19
Q
Is CL larger or smaller for drugs eliminated faster? How does this impact AUC?
A
- LARGER CL
- smaller AUC (less area under the curve/drug volume because it is excreted in urine faster)
20
Q
What does the AUC mean for oral (po) dosage forms?
A
After po, AUC reflects absorption and elimination.
21
Q
What are the abbreviations for oral clearance?
A
CLoral, CLpo, apparent clearance
22
Q
CLoral=
A
- Doseoral/AUC
- CL/F
F= bioavailibility
23
Q
What does a high CL/F mean?
A
- Either the drug is eliminated faster
- And/or there is poor oral absorption or significant hepatic metabolism, contributing to low bioavailibility.
24
Q
What CL terminology is from IV data?
A
- CL
- CLh
- CLr
- CLb
25
What CL terminology is from PO data?
CLoral or CLpo
26
What does a high Eh mean?
* Eh>0.7
* CLh=Q
* 100% of the drug enters the liver from the intestines.
* 90% of the drug is metabolized by the liver, meaning that only 10% reaches systemic circulation (the heart).
* This suggests a high hepatic extraction ratio, meaning that the drug undergoes extensive first-pass metabolism.
## Footnote
blood-flow dependent= Q
27
What does a low Eh drug mean?
* Eh<0.3
* CLh= Fu (CLintrinsic)
* 100% of the drug enters the liver from the intestines after oral administration.
* Only 10% is metabolized by the liver, meaning that 90% of the drug reaches systemic circulation (the heart).
* This suggests a low hepatic extraction ratio, meaning that the drug undergoes limited first-pass metabolism.
## Footnote
metabolism is capacity limited, changes in enzyme activity impact drug levels (enzyme inducers vs inhibitors)
28
How do we calculate the extraction ratio?
* X enters system, Y (mg) eliminated, X-Y is remaining drug amount.
Example
* 1 mg goes in, 0.3 eliminated, 0.7 mg remaining--> E= 0.3
29
What is the extraction ratio?
* A fraction of the drug eliminated by a drug-eliminating organ during single pass
* Efficiency of a drug-eliminating organ to eliminate a drug
* Values range from 0 to 1
* Drug-dependent parameter
* Higher E= eliminated faster
30
How do we calculate organ clearance?
Q(E)
* The volume of plasma from which a drug is completely eliminated by drug-eliminating organ per unit time
* Unit: volume/time
* Values range from 0 to plasma flow to the organ (Q)
* Drug-dependent parameter
31
What is the difference between Eh and CLh?
Eh
* A fraction of drug eliminated by liver during single pass
* Efficiency of liver to eliminate a drug
* Values range from 0 (no metabolism) to 1 (complete metabolism)
CLh
* Volume of plasma from which a drug is completely eliminated by liver per unit time
* Values range from 0 to hepatic plasma flow
* CLh= Qh(Eh)
Qh
* hepatic plasma flow
* 0.7 L/min (physiological value)
32
What does an Eh value around 1 mean?
CLh approaches Qh
33
What are some low <0.3 Eh drugs?
* **Theophylline**
* **Warfarin**
* Carbazepine
* Diazepam
* Naproxen
* Nitrazepam
* Phenobarbital
* Phenytoin
* Procainamide
* Salicylic Acid
* Valproic Acid
34
What are some intermediate Eh drugs (0.3-0.7)?
* Aspirin
* Quinidine
* Codeine
* Nifedipine
* Nortriptyline
35
What are some high Eh drugs (>0.7)?
* **Verapamil**
* Alprenolol
* Cocaine
* Desipramine
* Lidocaine
* Meperidine
* Morphine
* Nicotine
* Nitroglycerin
* Pentazocine
* Propoxyphene
* Propranolol
36
What characterizes low Eh drugs like warfarin?
* High protein binding
* Low enzyme activity against a drug limit hepatic elimination
37
What characterizes high Eh drugs?
* good substrates of drug-metabolizing enzymes
* protein binding does not limit metabolism
38
What is intrinsic clearance (CLint)?
* The natural ability of the liver to metabolize a drug, independent of binding restrictions (when drugs are in free forms)
* Unit: volume/time
* Values are greater than 0, but there is no upper limit
Large CLint
* drugs are rapidly metabolized by the liver when drugs are in the unbound (free) form
Small CLint
* drugs take longer to be metabolized even in the unbound form
Enzyme kinetics
* CLint is calculated from in vitro experiments using liver tissues. Have to use Michaelis-Menten constants.
39
How to calculate the rate of elimination (dA/dt)?
= -CL(Cp)
40
How to calculate the rate of metabolism?
= CLm(Cu)
which is equivalent to
= (Vmax(Cu))/(Km+ Cu)
In most cases Cu<
41
How do enzyme inducers and inhibitors impact CLint?
* Enzyme inducers increase the CLint of interacting drugs by inducing the expression of drug metabolizing enzymes.
* Enzyme inhibitors decrease the CLint of interacting drugs by inhibiting the activities of drug metabolizing enzymes.
42
What is the well-stirred model based on?
The study of how physiological changes or co-administered drugs can influence PK of drugs
43
Eh(well-stirred model)=
Eh= B/A+B
= (fu(CLint))/((Qh)(fu x CLint))
44
What factors effect hepatic plasma flow (Qh)?
* Decreased by diseases such as HF, liver disease and drugs like propranolol or beta blockers.
* Increased by food
45
What factors affect the CLint?
* Decreased by liver disease, dietary deficiencies, enzyme inhibiting drugs such as cimetidine.
* Increased by enzyme inducing drugs such as phenobarbital, rifampin, and environmental pollutants including polycyclic hydrocarbons (in cigarettes).
46
What factors affect fu?
Changes in plasma binding most significantly impact fu.
* Plasma proteins (e.g., albumin) are synthesized in the liver. Chronic liver diseases such as cirrhosis decrease circulating plasma protein concentrations.
* Changes in plasma binding can result from displacement of drugs from plasma proteins by other drugs with higher affinity for the same protein binding site, e.g., aspirin displaces warfarin (anticoagulant) from albumin.
47
What is CLh only affected by for low Eh drugs?
Changes in CLint and fu
## Footnote
CLh=fuCLint
48
What is CLh only affected by in high Eh drugs?
Only affected by changes in Qh.
## Footnote
CLh=Qh
49
# Drug-drug interaction with lidocaine and beta-blocker
Lidocaine's fe~0. What is the relationship between CL and CLh?
Lidocaine's fe ≈ 0 means that it is almost completely metabolized by the liver. Since it is a high EH drug, CLH ≈ QH, meaning its clearance is directly dependent on hepatic blood flow.
50
# Drug-drug interaction with lidocaine and beta-blocker
Does the Beta blocker influence Qh, fu, or CLint?
β-blockers influence QH (hepatic blood flow), which affects the clearance of high EH drugs.
51
# Drug-drug interaction with lidocaine and beta-blocker
What would the use of beta blockers do to CLh of antipyrine (a low EH drug)?
β-blockers would have little to no effect on antipyrine (a low EH drug) because its clearance is dependent on CLint rather than QH.
52
# Warfarin affected by rifampin
Which of QH, fu, or CLint does rifampin influence and in which direction?
Rifampin increases CLint by inducing liver enzymes (CYP450), leading to faster metabolism of warfarin.
53
# Warfarin affected by rifampin
Warfarin’s fe~0. What is the relationship between CL and CLH?
Warfarin's fe ≈ 0, meaning it is almost entirely cleared by the liver. Since it is a low EH drug, CLH = fu × CLint, meaning that increasing CLint will directly increase CLH.
## Footnote
CL=CLh
54
# Warfarin effected by rifampin
Assuming that rifampin does not affect Vd of warfarin, what is the effect of rifampin on warfarin t1/2?
If rifampin does not affect Vd, an increase in CL will lead to a decrease in half-life (t1/2) because t1/2 = 0.693/k
K=Vd(CL).
55
F=
**Fa(1-Eh)**
With 100% absorption,
F=1-Eh
F= Qh/((Qh+fu)(Clint))
## Footnote
Fa= fraction absorbed
56
What is the bioavailibility of a low Eh drug?
F=Qh/Qh
F=1
## Footnote
Since only a small fraction of the drug is metabolized in the liver, most of it reaches systemic circulation.
57
For a high Eh drug, what is the equation used to calc F?
F=Qh/((fu(CLint))
58
IF a drug is 100% metabolized, CL=?
CLh
59
What factors affect AUCpo for drugs with low Eh and high Eh?
* Low Eh: fu, CLint
* High Eh: fu, CLint
60
What factors affect AUCiv for drugs with low Eh and high Eh?
* Low Eh: fu, Clint
* High Eh: Qh
61
What is filtration?
From arterial bloodstream into the glomerulus
62
What is secretion (renal)?
from arterial bloodstream into the proximal tubule.
63
What is reabsorption (renal)?
from lumen of nephron into venous bloodstream (actively reabsorb nutrients)
64
Does filtration and secretion increase or decrease excretion?
Increase
65
Does reabsorption increase or descrease excretion?
Decrease
66
Describe renal excretion.
* 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.
* Approximately 20% of cardiac output, 1.1 L/min, goes to the kidneys. Of this volume, 10% is filtered in the glomerulus; this is the glomerular filtration rate (GFR=120 ml/min).
* Pores in the glomerulus permit the passage of most drug molecules but restrict passage of blood vells and plasma proteins. TF, only unbound drug is filtered.
* Over 90% of the filtered volume is reabsorbed in the renal tubules, with only 1-2 ml/min leaving the kidney as urine. A total of 1.5 L of filtrate is excreted as urine per day (i.e., urine flow=1-2 ml/min).
67
What is renal clearance?
* CLr
* the proportionality constant relating the rate of urinary excretion and plasma concentration of drug in the body (Cp)
* CLr= (total amount excreted unchanged into the urine)/AUCiv= fe(CL)
* dAe/dt= CLr(Cp)
68
Where does filtration occur?
The glomerulus
69
What does filtration depend on?
* Molecular Weight
* fu- unbound drug concentration in plasma
Small molecules and proteins are filtered readily, but high MW proteins are NOT filtered well.
70
Does bound drug in plasma water get filtered?
No; Only unbound drug in plasma water is filtered.
71
Rate of filtration=
fu(Cp)(GFR)=Cu(GFR)
72
How do we calc the CLr for a drug eliminated only by filtration?
CLr= fu(GFR)
When secretion added
* CLr>fu(GFR)
When Reabsorption added
* CLr
73
Where does secretion occur?
proximal tubule
74
What type of process is secretion?
Active carrier-mediated process; saturable. There are separate transporters for acids and bases from plasma into urine. In general, neutral drugs are not secreted.
75
What can we infer if the rate of excretion>rate of filtration?
* Infer that secretion has occurred.
* If CLR > fu ⋅GFR, then assume that secretion has occurred (reabsorption may have occurred, but secretion is greater).
76
What are characteristics of high renal excretion drugs?
| high Er
* Good substrates for renal transporters
* Dissociate rapidly from plasma proteins so as not to limit secretion
* Amount of secretion is dependent only on renal blood flow
77
What are the characteristics of low renal excretion drugs?
| low Er
* poor substrates for renal transporters
* Even though blood sits at the proximal tubule for 30 sec, transportation is the limiting step.
* Amount of secretion depends on unbound drug conc of drug in blood and is independent of renal blood flow (furosemide).
78
What are the two things that secretion may depend on based on Er?
(1) Plasma protein binding
(2) Kidney blood flow
79
What are two common organic acids actively secreted by the kidney?
* PCN
* Probenecid
80
Where does reabsorption occur?
Occurs along the length of the nephron
81
What type of process is reabsorption?
Passive process for exogenous products including drugs. Active process for many endogenous compounds, e.g., vitamins, electrolytes, amino acids, glucose (CLR of glucose = 0).
82
What can we infer if the rate of excretion
* Infer the reabsorption has occured
* If CLR < fu ⋅GFR, then reabsorption has occurred (secretion may have occurred, but reabsorption is greater).
83
What are the properties of drugs that impact renal reabsorption?
(1) Polarity of the drug
* Polar compounds are readily excreted, not reabsorbed
(2) Ionization of the drug
* Ionized cmpds are not reabsorbed
84
What are the physical factors that may impact renal reabsorption of drugs?
(1) Urine Flow
* High plasma protein binding decreases drug excretion
* Faster urine flow increases drug exretion.
* CLr= fu (urine flow)
(2) Urine pH
* Urine pH can widely range from 4.5 to 7.5 (avg 6.3)
* Variations due to forced acidification/alkalization, respiratory or metabolic acidosis/alkalosis, or drugs
* Acidification of the urine (decreased pH) promotes reabs of weak acids and promotes CLr of weak bases.
* Alkalinization of urine (increased pH) promotes reabsorption of weak bases and promotes CLr of weak acids.
85
What diuretic can make the urine alkaline?
Acetazolamide
86
What diuretic can make the urine acidic?
ammomium chloride
87
What other ions can change urine pH?
Sodium bicarb--> alkaline urine
Vit C--> Acidic urine
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