05 PK Excretion Eng

7/29/2019 05 PK Excretion Eng

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713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY

Dr. Korawuth Punareewattana

Pharmacokinetics: Drug Excretion

Topic 5

Faculty of Veterinary Medicine, Khon Kaen University


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Topic Contents Definition

Routes of excretion

Renal excretion

Processes involved in renal excretion

Ion trapping

High and low renal clearance

Biliary excretion

Pulmonary excretion

Mammary excretion

Salivary excretion


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Drug Excretion

Definiton

The removal of a drug molecule

from the body without chemical

modification.

Generally in urine,

but occasionally in bile

etc.


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Routes of excretion

Major routes

Renal (primary route)

Biliary Feces Pulmonary

Minor routesbut significance for

other reasons

Mammary - Delivery to baby

Salivary - Drug monitoring


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Kidney

Filtration

Acid Base99% of H

2

0 +

Lipid soluble

drugs

Plasma flow

650ml/min

Glomerular Fitration Rate(GFR)

125ml/min Urine

1ml/min

Active Secretion Reabsorption


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Processes involved in renal excretion: 1

Filtration

Passive process (Pressure driven)

20% of plasma volume is filtered

Small molecules - Yes

Large molecules No

Most proteins not filtered.

Drugs which are extensively protein bound will also not be filtered.


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Active secretion

Energy requiring

Two separate

mechanisms for

acids & bases

Saturable

Possible interactions

Competition for

transporters


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Active secretion

Acids

Furosemide

Penicillins

Probenecid

Bases

Quinine

Quaternary ammonium salts

Probenecid and penicillins share same mechanism.

- Probenecid competes with penicillins.

- Penicillin clearance reduced.


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Reabsorption

99% of water is reabsorbed

Lipid soluble drugs reabsorbed

along with the water.

Only very water soluble

molecules can be efficiently

excreted by the kidneys.


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Ion trapping

Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose. Sodium

bicarbonate may be given to make the urine alkaline

Urine Rest of body

pH 8.0 pH 7.4

Non-ionized Non-ionized

Ionized Ionized

Barbiturate moves into urine - eliminated from body.


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Renal clearance

The volume of

plasma completely

cleared of a specific

compound per unit

time and measured

as a test of kidney

function.

In medicine, the

clearance is a

measurement of the

renal excretion ability


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High renal clearance

Ifrenal clearance is greater than G.F.R.

Ex. - G.F.R. = 600 ml/min

- Renal clearance = 650 ml/min

then there must be active secretion.


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Low renal clearance

If clearance is much less than G.F.R. then either:

Not filtered

Extensively reabsorbed

e.g. antipyrine, thiopental


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Biliary excretion

Bile formed in large volumes in the liver

Most of the water re-absorbed

Concentrated bile stored in the gall

bladder

Bile secreted into the upper small

intestine


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Biliary excretion

Most drugs Mol Wt too low for efficient biliary excretion.

Conjugation to glucuronide

often increases Mol Wt sufficiently for biliary excretion.

Acetate or glycine generally too small.

Bile is significant route of excretion for:

Glucuronide conjugates (e.g. morphine)

Limited number of ionised drugs with very high Mol Wt


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Entero-hepatic circulation

Liver

FreeConjugates

in bile

Small intestineColon

ConjugatesFree

Mainly bacteria in colon that hydrolyse the conjugat


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Pulmonary excretion

Excretion via the lungs and breath.

Significant route of excretion for some volatile molecules

- especially anaesthetics (gas anesthesia).


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Mammary excretion - (milk)

No active secretion, just passive diffusion.

Concentration in milk reflects free concentration in blood

(apart from ion trapping).

Milk is slightly acid (pH 7.0) compared to blood (pH 7.4).


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Erythromycin in milk

Lipid

Blood (pH 7.4) Milk (pH 7.0)

Non-ionized Non-ionized

Ionized Ionized

Erythromycin concentrations approx 8 times higher in milk

than blood.


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Drugs in milk -clinical significance

The effect of the drug on the baby

Tetracyclines - incorporated into teeth which become weakened

and mottled.

Chloramphenicol - Bone marrow toxicity

Drug residues in milk products

Milk quality

Public health problems


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Excretion in Saliva

Significant because of possible use in drug monitoring.

Pharmacokinetic experiments often need serial blood samples (10 or more).

Ethical approval?

Saliva sampling is non-invasive.

Neutral molecules

salivary concentrations do reflect free concentrations in plasma.

Ionised drugs are a problem.

Saliva pH is variable

variable degree of ion trapping.

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