12-15 - Bioavailability & Clearance Flashcards
1
Q
Bioavailability
F
A
- Fraction of dose that reaches systemic circulation (the heart)
-
Absolute Bioavailability
- If the other dosage form is IV
- varies between 0 - 1
-
Relative Bioavilability
- If the refrence dosage form is something other than IV
- Ex. Tablet relative to solution
2
Q
Oral Bioavailability
F
A
- AUC/Dose for oral divided by AUC/Dose for IV
- AUC is proportional to dose in linear kinetics
- Determinants of F
- Intestinal Absorption = FA
- Hepatic Metabolism = FH
-
Intestinal metabolism = FG
- insignificant for most drugs
- ~some CYP450 in gut but insig.
- First pass effect - significant loss of drug during first pass through liver after ORAL admin.
3
Q
LOW F is due to?
A
HIGH hepatic metabolism
(EH) –> ( FH = 1-E<strong>H</strong> )
POOR Intestinal Absorption
(FA)
4
Q
Drug with poor dissolution
+
Anticholinergic
A
- Digoxin = poor dissolution drug
- Anticholinergic –> INCREASE retention time
- –> INCREASE extent of absorption
- –> INCREASE AUCpo of digoxin
- –> INCREASE F (bioavailability of digoxin)
5
Q
Well absorbed drug
+
Prokinetic drug
A
- Acetaminophen = well-absorbed~complete absorption
- Prokinetic –> INCREASE GI motility
- –> INCREASE rate of absorption
- drug simply is just absorbed faster, no more of it is absorbed
- –> does not change AUCpo
- drug is already well absorbed so AUC nor F change
- –> INCREASE rate of absorption
6
Q
Hapatic Metabolism
Enzyme Inducer
A
- Expression of hepatic CYP enzymes can be induced by drugs such as rifampin
- __Drug –> MORE ENZYMES
- –> LESS drug is absorbed
- more drug is metabolized hepatically
7
Q
Hepatic Metabolism
Enzyme Inhibitor
A
- CYP enzyme function can be impaired by drugs such as Cimetidine
-
less enzymes to metablize the drug
- –> MORE drug is absorbed
8
Q
Plasma
A
- We measure drug concentration in PLASMA
- Liquid component of blood, which blood cells are suspended
- ~55% of blood volume
- Contain vital proteins
- Fibrinogen
- Globulin
- Albumin
- Most drugs are found in plasma (bound or free)
-
Special drugs bind to RBC
- ex. tacrolimus / cyclosporine
9
Q
Plasma Concentration
vs
Blood Concentration
A
Cb/Cp = 0.5-0.6
- if drug does not bind to blood cells, this ratio sits between 0.5-0.6
- tacrolimus & cyclosporine have a ratio >15
- If you measure Clearance of Plasma Vs Blood
-
only thing different is the Vd
- Volume of distribution changes because there is a different amount of blood vs plasma
-
only thing different is the Vd
- For most drugs (that distribute in plasma)
- ClB > CL
- Because Cl = kel x Vd
10
Q
CL vs AUC
A
CLEARANCE** IS I**NVERSELY** RELATED TO **AUC
CLoral = Doseoral / AUCoral = CL/F
- If the clearance of a drug INCREASES
- –> AUC decreases
-
Large CL<strong>oral</strong> may indicate FASTER drug elimination
- and/or poor bioavailability
11
Q
Clearance = Elimination
A
CL = CLHepatic + CLRenal
- Theoretically, systemic clearance is the sum of all the organs clearances
- BUT the Liver & the Kidney are the major organs.
- Most drugs are eliminated by metabolism
- –> Metabolites go to the URINE
- Some drugs are unchanged in the urine.
12
Q
fe
A
fraction excreted unchanged into the urine
fe = Total drug excreted unchanged (AEinf) / Dose
= CLR / CL
CLR = CL x fe
- if 100% of a drug is found in the urine as metabolites*
- then the fe of the drug is ZERO*
13
Q
Hepatic Extraction Ratio
EH
A
- Fraction of Drug eliminated by liver during single pass
- efficiency of liver to eliminate a drug
-
Range from 0-1
- __1 = complete metabolism
- drug dependent parameter
EH = CLH / QH
High EH drugs > 0.7
Low EH drugs < 0.3
14
Q
Hepatic Clearance
CLH
A
CLH = EH x QH
QH = Hepatic Plasma Flow (L/min)
- Volume of plasa from which a drug is completely eliminated by the liver PER UNIT TIME
- Values range from 0-QH
*
15
Q
Low EH Drugs
< 0.3
A
-
Theophylline
- intermediate protein binding
-
Warfarin
- 99% protein binding
- Increasing free fraction of warfarin
- has SIGNIFICANT effects on its EH
CLH = fu x CLint
16
Q
High EH Drugs
> 0.7
A
-
Verapamil
- 90% - high protein binding
-
Increasing free fraction of verapamil
- –> INSIGNIFICANT effects on EH
CLH = QH
17
Q
Intrinsic Clearance
CLint
A
CLint = Vmax / Km
- Reflects the natural ability of the liver to metabolize a drug
- INDEPENDENT OF BINDING RESTRICTIONS
- Values >0, no upper limit
- Drugs of LARGE CLint = Good Substrates
- Rapidly Metabolized by the liver when drugs are in unbound form
-
Drugs of SMALL CLint = BAD SUBSTRATE
- Take longer to be metabolized even when the drugs are in unbound form
- Calculated from IN VITRO experiments (involve liver tissue)
18
Q
Enzyme Inducers
A
INCREASE CLint of Interacting drugs
INDUCE protein expression of metabolizing enzymes
–> drugs metabolized more, lower AUC & F
ex. phenobarbital / rifampin
19
Q
Enzyme Inhibitors
A
DECREASE CLint of interacting drugs
INHIBIT function of drug metabolizing enzymes
–> drug concentration (AUC) & F increases
ex. erythromycin / cimetidine
20
Q
Factors Affecting
QH
(Hepatic Plasma Flow)
A
- INCREASED BY FOOD
-
Decreased by disease states:
- Heart failure / liver disease
-
Decreased by drugs:
- Beta blocker = propranolol
21
Q
Factors Affecting
CLint
(Hepatic Enzyme activity / clearance )
A
-
Increased by ENZYME INDUCING drugs:
- Phenobarbital
- Rifampin
- Environmental pollutants = cigarettes
-
Decreased by:
- Liver disease
- Dietary Deficiency
-
Enzyme INHIBITING drugs:
- cimetidine
22
Q
Factors Affecting
fu
(fraction unbound to plasma proteins)
A
-
Increased by drugs that displace plasma binding of another drug with higher affinity for the same binding site
- Ex. Aspirin displaces Warfarin
- Less warfarin can be bound to plasma protein
- –> INCREASE in fraction of unbound drug
-
Increased by liver diseases
- Plasma proteins (albumin) are synthesized in liver
- –> less plasma protein
- –> INCREASE of unbound drug
- Plasma proteins (albumin) are synthesized in liver
23
Q
Factors Affecting
Bioavailability (F)
A
- We assume* NO GI Metabolism ( EG = 0 ) &
- Drug is 100% absorbed ( FA = 1 )*
F = (1 - EH)
-
for High EH Drug:
- F is affected by changes in CLint / Fu / QH
- F is low
- for Low EH Drug:
- F is close to 1
- Not effected by changes in CLint / Fu / QH
24
Q
Rifampin
Phenobarbital
A
Enzyme INDUCERS
INCREASE CLint of Interacting drugs
INDUCE protein expression of metabolizing enzymes
–> drugs metabolized more, lower AUC & F
25
**Erythromycin**
**Cimetidine**
***ENZYME INHIBITORS***
*_DECREASE CLint_* of interacting drugs
*INHIBIT* function of drug metabolizing enzymes
--\> drug concentration (AUC) & F increases
26
Factors Affecting
## Footnote
**AUCIV**
**AUCIV = DoseIV / CL**
* **for High EH drug:**
* **CL = QH**
* **QH affects** **AUCIV**
* *****for low EH drug:*
* *CL = fu x CLint*
* *fu & CLint affect **AUCIV***
27
Factors Affecting
## Footnote
**AUCpo**
**AUCpo =** **Dosepo / (CL/F)**
For both High / *Low EH Drugs:*
**fu & CLint**
28
**Renal Excretion**
Drug is brought out to the **--\> URINE** from the bloodstream
* **Filtration**
* Arterial bloodstream --\> Glomerulus
* Pores in the glomerulus permit passage of most drugs (restrict blood cells / plasma proteins)
* Only UNBOUND drug is filtered
* **Secretion**
* Arterial bloodstream --\> Proximal Tubule
* Only 1-2ml/min leave the kidney as urine
* 90% of volume is _reabsorbed_
* ___lumen of nephron --\> venous bloodstream_
29
**Renal Clearance**
**CLR**
**CLR = fe x CL**
30
**Filtration**
For a drug that is eliminated **ONLY** by **filtration**
**CLR = fu x GFR**
**EQUALS**
* Occurs @ Glomerulus
* Depends on:
* **Molecular Weight**
* ****Small molecules/proteins are readily filtered
* Large/high MW proteins are nto filtered well
* Insulin, albumin, myoglobulin
* **fu **(unbound drug conc. in plasma)
* only unbound drug is filtered
31
**Secretion Dominant**
**CLR \> fu x GFR**
**Greater Than \>**
* from arterial bloodstream --\> **proximal tube**
* INCREASE EXCRETION
* Active carrier-mediated process = Saturable
* Seperate transporters for Acids / Bases
* neutral drugs are typically not secreted
32
**Reabsorption Dominant**
**CLR \< fu x GFR**
**Less Than \<**
* ****from lumen of nephron --\> venous blood stream
* *DECREASES excretion*
33
High Renal Excretion Drugs
**( High ER )**
**Good Substrates** for renal transporters
**Dissociate Rapidly** from plasma proteins (do not limit secretion)
**Dependent only on Renal Blood Flow**
*ex. para-amino huppuric acid (**ER ~ 1)***
34
Low Renal Excretion Drugs
**( Low ER )**
*_Poor Substrates_* for renal transporters
*Sits @ proximal tubule for ~ 30 seconds*
_Transportation is the limiting step_
Amount of secretion depends on _unbound concentration of drug in blood_ **( fu )**
* independent of renal blood flow*
* ex. furosemide*
35
Drugs actively **Secreted** By the kidney
* Organic Acids
* Loop Diuretics , Methothrexate, Nitrofurantoin
* Salicylates, Sulfonamides, Thiazide diuretics
* **Penicillins / Probenecid**
* ****2 compete for the same transporter
* Probenecid *DECREASES* the CLR of amoxicillin
* --\> **INCREASE** the concentration of amox.
* Organic Bases
* Amatadine, cimetidine (enzyme inhibitor)
* dopamine, morphine, psudophedrine, amiloride
36
**Reabsorption**
if rate of excretion \< rate of filtration, reabsorption is dominant:
**CLR \< fu x GFR**
* occurs along _length of nephron_
* __associated w/ reabsorption of water
* **PASSIVE PROCESS** for EXOgenous products (drugs)
* *active process for endogenous compounds*
* **Factors affecting renal absorption of drugs:
* Properties of the drug:
* **Polarity & Ionization**
* Physiological factors
* **Urine Flow & Urine pH**
37
**Drug Properties**
affect on Reabsorption
* **Polarity**
* ****Polar compounds are NOT reabsorbed
* high logP
* **Ionization**
* ****ionized compounds are NOT reabsorbed
* charged molecules
38
**Physiological Factors**
affect on Reabsorption
* **Urine Flow**
* **Faster** Urine Flow **--\> Increased** drug excretion
* if drug is extensively reabsorbed:
**CLR = fu x Urine Flow**
* **Urine pH** ( varies from 4.5-7.6 , avg 6.3 )
* Important for nonpolar drugs that are:
* **weak acids ( salicylates )**
* **weak bases ( amphetamine, ephedrine )**
* *****Alkalize urine*
* *Acetazolamide / sodium bicarb*
* _Acidify urine_
* _Ammonium chloride / vitamin C_
* _(diuretics)_
39
Reabsorption:
## Footnote
**Acidification of Urine**
Ammonium Chloride / Diuretics / Vitamin C
*DECREASE pH of urine*
* **Promotes reabsorption of weak ACIDS**
* **--\> INCREASE** weak acid drug concentration
* Promotes CLR of weak _bases_
* __--\> *DECREASE* weak base drug concentration
40
Reabsorption:
## Footnote
**Alkalinization of Urine**
Acetazolamide / Sodium Bicarbonate
**INCREASE** pH of urine
* Promotes reabsorption of weak _bases_
* **--\> INCREASE** weak _base_ drug concentration
* Promotes CLR of weak **acid**
* __--\> *DECREASE* weak **acid** drug concentration
41
**Acetazolamide**
**Sodium Bicarbonate**
**_ALKALIZE URINE_**
**INCREASE** **pH** of urine
* Promotes CLR of **weak acid**
* *Promotes reabsorption of _weak bases_*
42
**Ammonium Chloride (Diuretics)**
**Vitamin C**
**ACIDIFY Urine**
*DECREASE pH of urine*
* Promotes CLR of _weak bases_
* Promotes reabsorption of **weak acids**
43
Reabsorption:
## Footnote
**Strong Acids / _Bases_**
pKa \<3
pKa \> 12
completely ionized over urine pH range
therefore...**undergo little reabsorption**
44
**fe = 0**
**fe = 0**
**"Elimination is MAINLY by HEPATIC metabolism"**
**=**
**"Urinary Excretion is Negligable"**
**CLH = CL**
45
Propranolol
| (Beta Blocker)
* DECREASES QH*
* Decreases* the hepatic blood flow
46
