Topic 5

Pharmacokinetics: Drug Excretion

713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY Dr. Korawuth Punareewattana

Faculty of Veterinary Medicine, Khon Kaen University

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

Drug Excretion
Definiton The removal of a drug molecule from the body without chemical modification.
Generally in urine, but occasionally in bile etc.

Routes of excretion
Major routes Renal (primary route) Biliary Feces Pulmonary Minor routes but significance for

other reasons Mammary - Delivery to baby Salivary - Drug monitoring

Kidney
Glomerular Fitration Rate (GFR) 125ml/min

Urine 1ml/min

Plasma flow 650ml/min

Acid

Base

99% of H20 + Lipid soluble drugs

Filtration

Active Secretion

Reabsorption

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.

Processes involved in renal excretion: 2

Active secretion
Energy requiring
Two separate

mechanisms for acids & bases Saturable Possible interactions Competition for transporters

Processes involved in renal excretion: 2

Active secretion
Acids Furosemide Penicillins Probenecid Bases Quinine Quaternary ammonium salts

Probenecid and penicillins share same mechanism. - Probenecid competes with penicillins. - Penicillin clearance reduced.

Processes involved in renal excretion: 3

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.

Ion trapping
Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose. Sodium bicarbonate may be given to make the urine alkaline
Urine pH 8.0 Non-ionized Rest of body pH 7.4 Non-ionized

Ionized

Ionized

Barbiturate moves into urine - eliminated from body.

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

High renal clearance

If renal 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.

Low renal clearance

If clearance is much less than G.F.R. then either: Not filtered Extensively reabsorbed e.g. antipyrine, thiopental

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

Biliary excretion
Similar to kidneys Lipid soluble drugs filter initially, but get re-absorbed along with the bulk of the water. Not excreted efficiently. Acids and bases have active secretion mechanisms BUT only works effectively if Mol Wt high enough. Limit varies for different species. (>300-500 for humans)

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

Entero-hepatic circulation

Free
Liver

Conjugates in bile

Free Colon

Conjugates Small intestine

Mainly bacteria in colon that hydrolyse the conjugate

Pulmonary excretion
Excretion via the lungs and breath. Significant route of excretion for some volatile molecules - especially anaesthetics (gas anesthesia).

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).

Erythromycin in milk
Blood (pH 7.4) Non-ionized Milk (pH 7.0) Non-ionized

Ionized
Lipid

Ionized

Erythromycin concentrations approx 8 times higher in milk than blood.

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

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.