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Kinetics Midterm 2 > 12-15 - Bioavailability & Clearance > Flashcards

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
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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.
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3
Q

LOW F is due to?

A

HIGH hepatic metabolism

(EH) –> ( FH = 1-E<strong>H</strong> )

POOR Intestinal Absorption

(FA)

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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)
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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
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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
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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
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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
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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
  • For most drugs (that distribute in plasma)
    • ClB > CL
    • Because Cl = kel x Vd
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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
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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.
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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*
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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

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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
    *
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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

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16
Q

High EH Drugs

> 0.7

A
  • Verapamil
    • 90% - high protein binding
    • Increasing free fraction of verapamil
      • ​–> INSIGNIFICANT effects on EH

CLH = QH

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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)
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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

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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
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
Q

Erythromycin

Cimetidine

A

ENZYME INHIBITORS

DECREASE CLint of interacting drugs

INHIBIT function of drug metabolizing enzymes

–> drug concentration (AUC) & F increases

26
Q

Factors Affecting

AUCIV

A

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
Q

Factors Affecting

AUCpo

A

AUCpo = Dosepo / (CL/F)

For both High / Low EH Drugs:

fu & CLint

28
Q

Renal Excretion

A

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
Q

Renal Clearance

CLR

A

CLR = fe x CL

30
Q

Filtration

A

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
Q

Secretion Dominant

A

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
Q

Reabsorption Dominant

A

CLR < fu x GFR

Less Than <

  • ​from lumen of nephron –> venous blood stream
  • DECREASES excretion
33
Q

High Renal Excretion Drugs

( High ER )

A

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
Q

Low Renal Excretion Drugs

( Low ER )

A

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
Q

Drugs actively Secreted By the kidney

A
  • 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
Q

Reabsorption

A

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
Q

Drug Properties

affect on Reabsorption

A
  • Polarity
    • ​Polar compounds are NOT reabsorbed
    • high logP
  • Ionization
    • ​ionized compounds are NOT reabsorbed
    • charged molecules
38
Q

Physiological Factors

affect on Reabsorption

A
  • 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
Q

Reabsorption:

Acidification of Urine

A

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
Q

Reabsorption:

Alkalinization of Urine

A

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
Q

Acetazolamide

Sodium Bicarbonate

A

ALKALIZE URINE

INCREASE pH of urine

  • Promotes CLR of weak acid
  • Promotes reabsorption of weak bases
42
Q

Ammonium Chloride (Diuretics)

Vitamin C

A

ACIDIFY Urine

DECREASE pH of urine

  • Promotes CLR of weak bases
  • Promotes reabsorption of weak acids
43
Q

Reabsorption:

Strong Acids / Bases

A

pKa <3

pKa > 12

completely ionized over urine pH range

therefore…undergo little reabsorption

44
Q

fe = 0

A

fe = 0

“Elimination is MAINLY by HEPATIC metabolism”

=

“Urinary Excretion is Negligable”

CLH = CL

45
Q

Propranolol

(Beta Blocker)

A
  • DECREASES QH*
  • Decreases* the hepatic blood flow

Kinetics Midterm 2 (4 decks)

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