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Clearance From A Physiologic Perspective Chemical Clearance from the Body. Objectives for Today. Problems / Questions & Review concerning Chemical Distribution …? A Physiologic View of Chemical Clearance from the Body Develop a definition for Clearance. Clearance.

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slide1
Clearance

From A Physiologic Perspective

Chemical Clearance from the Body

Objectives for Today

  • Problems / Questions & Review concerning
  • Chemical Distribution …?
  • A Physiologic View of
  • Chemical Clearance from the Body
  • Develop a definition for Clearance.
slide2
Clearance

With time, where does the drug go?

Why are drugs lost from the body?

How are drugs lost from the body?

Based on random flow?

Like the elimination of an

coloured gas or odour from a room

or …?

slide3
Blood Flows1

Tissue Weight % Blood % Cardiac

or (kg) of Flow Output3

Organ IBW (mL/min)

Kidneys 0.16 0.23 1200 23

Adrenals 0.011 0.02 65 1.2

Thyroid 0.03 0.04 165 3.2

Brain 1.35 1.93 729 14

Liver 1.5 2.14 3002 5.8

Muscle 28 40 850 16

Skin 18 26 260 5.0

Fat 10 15 105 2.0

  • Spector, WS. Handbook of Biological Data
  • Includes only arterial flow; total equals about 1500 mL/min. (25%)
  • Cardiac Output / 70 kg = 5-6 L/min [85 mL/min/kg]
slide4
Clearance

With time, where does the drug go?

Organs are strategically arranged

(liver – to deal with entry & elimination

of compounds and are well perfused tissues.

If a drug is eliminated by an organ

(kidney or liver),

the organ will have access to a greater

amount of drug if a larger percentage of drug

is found in the blood / plasma or serum.

Theophylline 9.8%

Levo: 3.5% / 4.2%

Cipro: 2.9 %

Cyclosporin: 0.15%

slide5
Clearance

With time, where does the drug go?

Organs are strategically arranged

(liver – to deal with entry & elimination

of compounds and are well perfused tissues.

The blood emerging

from an eliminating organ

has a lower concentration

than the blood entering the organ.

This effectively dilutes

the drug concentration

in the primary storage area

… the rest of the body.

slide6
Focus on an Eliminating Organ

Pump

Clearing Chamber

Blood leaving the organ has a lower

drug concentration than drug entering.

Drug is “cleared” by the organ.

The efficiency of Removal is

quantified by the Extraction Ratio [ER].

slide7
Focus on an Eliminating Organ

Ca

Cv

Extraction Ratio can be viewed

as the proportion of drug removed

during passage through the organ.

slide8
Focus on an Eliminating Organ

Ca

Cv

Extraction Ratio can be viewed

as the proportion of drug removed

during passage through the organ.

At constant concentration (steady – state)

extraction can be estimated from the

difference between arterial and venous concentrations.

ER = [ (Ca – Cv) / Ca ]

where Ca is the concentration

in the artery on entry to the organ

and and Cv is the concentration

in the vein on exit from the organ

slide9
Focus on an Eliminating Organ

Pump

Clearing Chamber

Clearance of drug is dependant on 2 factors:

Efficiency of Removal [ER]

and

The rate at which drug can be

delivered to the organ [Flow Rate: Q].

Clearance = Q x ER (mL/min)

slide10
Focus on an Eliminating Organ

At constant concentration (steady – state)

clearance can be estimated from blood flow

and the difference between

arterial and venous concentrations.

ClH = Q [ (Ca – Cv) / Ca ] = Q*ER

or

Cl = Q x ER

where ER is the Extraction Ratio

and Q is organ blood flow.

When we focus on a single organ,

Hepatic Clearance would be symbolized by ClH

and Renal Clearance by CLR

slide11
Focus on an Eliminating Organ

When we focus on a single organ,

Hepatic Clearance would be symbolized by ClH

and Renal Clearance by CLR …

ClTOTAL = ClHEPATIC + ClRENAL + ClLUNG

Clearance as the units of Volume per time

(mL/min)

Definition:

Clearance:

The volume of distribution volume of the sampled fluid

from which drug is irreversibly removed per unit time.

slide12
Focus on an Eliminating Organ

How Efficient is a Normal Kidney

in removing Creatinine?

Cardiac Output = 85 mL/kg/min 70 kg male

Creatinine Clearance = ~ 120 mL/min (serum)

QRBLOOD = 25% CO

slide13
Focus on an Eliminating Organ

How Efficient is a Normal Kidney

in removing Creatinine?

Cardiac Output = 85 mL/kg/min 70 kg male

Creatinine Clearance = ~ 120 mL/min (serum)

QRBLOOD = 25% CO

= 0.25 (85)

= 21.25 mL/min/kg

QRSERUM = QRBLOOD

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide14
Focus on an Eliminating Organ

How Efficient is a Normal Kidney

in removing Creatinine?

Cardiac Output = 85 mL/kg/min 70 kg male

Creatinine Clearance = ~ 120 mL/min (serum)

QRBLOOD = 25% CO

= 0.25 (85)

= 21.25 mL/min/kg

QRSERUM = QRBLOOD (0.55)(70)

= 820 mL/min (serum)

ER =

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide15
Focus on an Eliminating Organ

How Efficient is a Normal Kidney

in removing Creatinine?

Cardiac Output = 85 mL/kg/min 70 kg male

Creatinine Clearance = ~ 120 mL/min (serum)

QRBLOOD = 25% CO

= 0.25 (85)

= 21.25 mL/min/kg

QRSERUM = QRBLOOD (0.55)(70)

= 820 mL/min (serum)

ER = 120/820 = 0.146

or 14.6%

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide16
Focus on an Eliminating Organ

How Efficient is a Normal Kidney

in removing Ciprofloxacin?

Cardiac Output (Renal)= 820 mL/min (serum)

Cipro Clearance = 35 L/hour (serum)

=

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide17
Focus on an Eliminating Organ

How Efficient is a Normal Kidney

in removing Ciprofloxacin?

Cardiac Output (Renal)= 820 mL/min (serum)

Cipro Clearance = 35 L/hour (serum)

= 583 mL/min

QRSERUM = QRBLOOD

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide18
Focus on an Eliminating Organ

How Efficient is a Normal Kidney

in removing Ciprofloxacin?

Cardiac Output (Renal)=820 mL/min (serum)

Cipro Clearance = 35 L/hour (serum)

= 583 mL/min

QRSERUM = QRBLOOD (0.55)(70)

= 820 mL/min (serum)

ER =

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide19
Focus on an Eliminating Organ

How Efficient is a Normal Kidney

in removing Ciprofloxacin?

Cardiac Output (Renal)= 820 mL/min (serum)

Cipro Clearance = 35 L/hour (serum)

= 583 mL/min

QRSERUM = QRBLOOD (0.55)(70)

= 820 mL/min (serum)

ER = 583/820 = 0.71

or 71%

Very efficient

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide20
Male Acute Community Acquired Pneumonia

Physiologic Approach

to Cipro Pharmacokinetics

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

Male with Pneumonia

Given the clearance of ciprofloxacin,

how much drug is required each day

to maintain an average concentration

of 2 mg/L? (peaks of 3-4; troughs ~0.5)

Age: 45 yr

Weight: 80 kg

Drug: Ciprofloxacin

Serum ciprofloxacin concentrations

average 2 g/mL (mg/L)

Cipro Volume: 1.5 L/kg

Cipro Am’t in body:

Cipro Clearance:

slide21
Male Acute Community Acquired Pneumonia

Physiologic Approach

to Cipro Pharmacokinetics

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

Male with Pneumonia

Given the clearance of ciprofloxacin,

how much drug is required each day

to maintain an average concentration

of 2 mg/L? (peaks of 3-4; troughs ~0.5)

Age: 45 yr

Weight: 80 kg

Drug: Ciprofloxacin

Serum ciprofloxacin concentrations

average 2 g/mL (mg/L)

Cipro Volume: 1.5 L/kg

Cipro Am’t in body: = 80 x 1.5 x 2

= 240 mg

Cipro Clearance: = 35 L/hr

= 840 L/day

slide22
Male Acute Community Acquired Pneumonia

Physiologic Approach

to Cipro Pharmacokinetics

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

Male with Pneumonia

Given the clearance of ciprofloxacin,

how much drug is required each day

to maintain an average concentration

of 2 mg/L? (peaks of 3-4; troughs ~0.5)

Age: 45 yr

Weight: 80 kg

Cipro Clearance: = 840 L/day

Average concentration over a day

2 mg/L

Dose required to maintain [ ]

= 2 (840) mg

= 1680 mg/day

slide23
Focus on an Eliminating Organ

How Efficient is a Normal Liver

in removing Theophylline?

Cardiac Output = 6.0 L/min

Proportion of CO to the Liver = 25%

Liver Blood Flow = 1.5 L/min

Proportion of Blood as Serum = 55%

Liver Serum (plasma) Flow = 1.5 L/min

= 0.82 L/min

OR = 820 mL/min

Cardiac Output = 85 mL/kg/min 70 kg male

Proportion of Blood as Serum = 55%

Liver Serum (plasma) Flow

= 85 * 70 * 0.55 * 0.25

= 818.12 mL/min

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide24
Focus on an Eliminating Organ

How Efficient is a Normal Liver

in removing Theophylline?

Cardiac Output = 6.0 L/min (Blood)

Liver Plasma Flow = 820 mL/min/70 kg male

Theophylline: 85% metabolized

15% excreted unchanged

Total clearance ~ 0.7 mL/min/kg

= 50 mL/min (serum)

Hepatic Clearance ClH =

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide25
Focus on an Eliminating Organ

How Efficient is a Normal Liver

in removing Theophylline?

Cardiac Output = 6.0 L/min (Blood)

Liver Plasma Flow = 820 mL/min/70 kg male

Theophylline: 85% metabolized

15% excreted unchanged

Total clearance ~ 0.7 mL/min/kg

= 50 mL/min (serum)

Hepatic Clearance ClH = 50(0.85)

= 42.5 mL/min

QHBLOOD = 820 mL/min (serum)

ER =

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

slide26
Focus on an Eliminating Organ

How Efficient is a Normal Liver

in removing Theophylline?

Cardiac Output = 6.0 L/min (Blood)

Liver Plasma Flow = 820 mL/min/70 kg male

Theophylline: 85% metabolized

15% excreted unchanged

Total clearance ~ 0.7 mL/min/kg

= 50 mL/min (serum)

Hepatic Clearance ClH = 50(0.85)

= 42.5 mL/min

QHBLOOD = 820 mL/min (serum)

ER = 42.5/820 = 0.052

or 5.2%

Equations

Conc = Dose / V

V = Dose/Conc

Cl = Q x ER

ER = Cl / Q

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