04/11/23 1

DRUG EXCRETION

ByA. S. Adebayo, Ph.D.

AndMarcia Williams

04/11/23 2

Renal excretion

The major organ for the excretion of drugs is the KIDNEY.

The functional unit of the kidney is the nephron.

04/11/23 3

One Nephron of the Kidney

04/11/23 4

Major Excretory Processes in the Nephron

Glomerular filtration Increase drug conc. in lumen

Tubular secretion Increases drug conc. in lumen

Tubular re-absorption Decreases drug conc. in lumen

04/11/23 5

Glomerular filtration

Molecules of low molecular weight are filtered out of the blood

Most drugs are readily filtered from the blood unless they are tightly bound to plasma protein or have been incorporated into red blood cells.

Normal GFR in healthy individuals is 110 to 130 ml/min.

About 10% of the blood which enters the glomerulus is filtered.

04/11/23 6

Glomerular filtration (Cont)

This filtration rate is often measured by determining the renal clearance of inulin.

Inulin is readily filtered in the glomerulus, and is not subject to tubular secretion or re-absorption. Thus inulin clearance is equal to the GFR.

Most drugs are filtered from blood in the glomerulus but the overall renal excretion is controlled by what happens in the tubules.

More than 90% of the filtrate is reabsorbed. 120 ml/min is 173 L/day. Normal urine output is much less than this, about 1 to 2 liter per day.

04/11/23 7

Tubular secretion

This is an active process. The process requires a carrier and a supply of

energy; also subject to competitive inhibition (e.g. Penicillin & Probenecid), and is saturable.

Not affected by pH. Drugs or compounds which are extensively

secreted, such as p-aminohippuric acid (PAH), may have clearance values approaching the renal plasma flow rate of 425 to 650 ml/min, and are used clinically to measure this physiological parameter

04/11/23 8

Tubular re-absorption

Passive or active re-absorption of lipid soluble drugs take place in the distal tubule.

Drugs which are present in the glomerular filtrate can be reabsorbed in the tubules.

Active re-absorption Seen with high threshold endogenous

substances or nutrients that the body needs to conserve such as electrolytes, glucose, vitamins, amino acids etc.

Uric acid is also actively re-absorbed. Reabsorption is inhibited by a uricosoric agent, through competitive inhibition.

Very few drugs undergo reabsorption actively.

04/11/23 9

Tubular re-absorption

Passive reabsorption The membrane is readily permeable to

lipids, so filtered lipid-soluble substances are extensively reabsorbed.

At this site, much of the water in the filtrate has been reabsorbed and therefore the concentration gradient is now in the direction of re-absorption.

Thus, if a drug is non-ionized or in the unionized form it may be readily reabsorbed.

04/11/23 10

Effect of Urine pH on tubular re-absorption

Many drugs are either weak bases or acids and therefore the pH of the filtrate can greatly influence the extent of tubular re-absorption for many drugs.

When urine is acidic, weak acid drugs tend to be reabsorbed. Alternatively when urine is more alkaline, weak bases are more extensively reabsorbed

These changes can be quite significant as urine pH can vary from 4.5 to 8.0 depending on the diet (e.g. meat can cause a more acidic urine) or food rich in carbohydrate ↑ pH or drugs (which can increase or decrease urine pH).

04/11/23 11

Alteration of Urine pH Excretion of some drugs can be increased by

suitable adjustment of urine pH e.g. pentobarbital (a weak acid) overdose may be treated by making the urine more alkaline with sodium bicarbonate injection.

Effective if the drug is extensively excreted as the unchanged drug (i.e. fe ≈ 1).

If the drug is extensively metabolized, then alteration of kidney excretion may not significantly alter the overall drug metabolism.

The effect of pH change on tubular re-absorption can be predicted by consideration of drug pKa according to the Henderson-Hesselbalch equation.

04/11/23 12

Drugs pKa Nature Urine pH Valaes4.5%Ionized

Urine pH Valves4.5ClR

Urine pH Valves6.3%Ionized

Urine pH Valves6.3ClR

Urine pH Valves7.5%Ionized

Urine pH Valves7.5ClR

Acids

A 2.0 Strong 99.7 0.001 99.99 0.8 100.0 1.26

B 6.0 Weak 3.0 0.04 66.6 0.115 97.0 1.25

C 10.0 V.Weak

0.0 0.99 0.02 0.99 0.3 1.0

BASES

D 12.0 Strong 100.0 794.3 100.0 12.6 99.99 0.79

E 8.0 Weak 99.9 635.2 98.0 10.26 76.0 0.83

F 4.0 V.Weak

24.0 1.32 0.0 1.0 0.0 1.0

04/11/23 13

Effect of Drug pka on renal clearance

The significance of pH dependent excretion for any particular compound is greatly dependent upon its pKa and lipid solubility.

A characteristic of drugs, pKa values govern the degree of ionization at a particular pH.

A polar and ionized drug will be poorly reabsorbed passively and excreted rapidly

Reabsorption is also affected by the lipid solubility of drug; an ionized but lipophilic drug will be reabsorbed while an unionized but polar one will be excreted.

04/11/23 14

Effect of Drug pka on renal clearance

The combined effect of urine pH and drug pKa and lipid solubility on reabsorbed of drugs is summarized as follows:

An acidic drug eg. penicillin or a basic drug eg. gentamicin are polar in their unionized form, is not reabsorbed passively, irrespective of the extent of ionization in urine.

Excretion of such drugs is the sum of rate of filtration and rate of active secretion.

04/11/23 15

Effect of Drug pka on renal clearance

Very weakly acidic, nonpolar drugs (pKa>8.0) such as phenytoin or very weakly basic, nonpolar drugs (pKa< 6.0) such as propoxyphene are mostly unionized throughout the entire range of urine pH. The rate of excretion of such drugs is always low and insensitive to pH of urine.

A strongly acidic drug (pKa ≤ 2.0) such as cromoglycic acid or a strongly basic drug (pKa ≥ 12.0) such as guanethidine, is completely ionized at all values of urine pH and are , therefore, not reasorbabed. Their rate of excretion is always high and insensitive to pH of urine.

04/11/23 16

Effect of Drug pka on renal clearance

Only for an acidic drug in the pKa range 3 – 8 eg NSAIDS and basics drug in pka range 6 – 12 eg morphine analogs and tricyclic antidepressants is the extent of re-absorption greatly dependent on urine pH

04/11/23 17

Renal clearance

A quantitative method of describing the renal excretion of drugs.

Renal clearance can be calculated as part of the total body clearance for a particular drug.

Renal clearance can be used to investigate the mechanism of drug excretion.

If the drug is filtered but not secreted or reabsorbed the renal clearance will be about 120 ml/min in normal subjects.

04/11/23 18

Renal clearance (Cont.)

If the renal clearance is less than 120 ml/min then we can assume that at least two processes are in operation, glomerular filtration and tubular re-absorption.

If the renal clearance is greater than 120 ml/min then tubular secretion must be contributing to the elimination process.

It is also possible that all three processes are occurring simultaneously.

04/11/23 19

Renal clearance (Cont.)

04/11/23 20

Renal clearance (Cont.)

Renal clearance values can range from 0 ml/min ( glucose) to a value equal to the renal plasma flow of about 650 ml/min (for compounds like p-aminohippuric acid).

We can calculate renal clearance using the pharmacokinetic parameters kel and Vd.

CLrenal = kel * Vd.

04/11/23 21

Renal clearance We can also calculate

renal clearance by measuring the total amount of drug excreted over some time interval and dividing by the plasma concentration measured at the midpoint of the time interval

04/11/23 22

Hemodialysis Hemodialysis or ‘artificial kidney’ therapy is

used in renal failure to remove toxic waste material normally removed by the kidneys, from the patient’s blood.

Involves diversion of blood externally and allowed to flow across a semi-permeable membrane bathed with an aqueous isotonic solution.

Nitrogenous waste products and some drugs will diffuse from the blood, thus these compounds will be eliminated.

04/11/23 23

Applicability of Hemodialysis Particularly important with drugs which:

Have good water solubility; Are not tightly bound to plasma protein; Are smaller (less than 500) molecular

weight; and Have a small apparent volume of

distribution. Not very useful for drugs which are tightly

bound or extensively stored or distributed into tissues.

04/11/23 24

Biliary excretion

The liver secretes 0.25 to 1 liter of bile each day.

Some drugs and their metabolites are excreted by the liver into bile including anions, cations, and non-ionized molecules containing both polar and lipophilic groups with molecular weight greater than about 300.

Molecular weights around 500 appear optimal for biliary excretion in humans.

04/11/23 25

Biliary excretion (Cont.)

Lower molecular weight compounds are reabsorbed before being excreted from the bile duct.

Conjugates, glucuronides (drug metabolites) are often of sufficient molecular weight for biliary excretion.

This can lead to biliary recycling. Indomethacin is one compound which undergoes this form of recycling.

04/11/23 26

Enterohepatic Recycling

04/11/23 27

Cp versus Time showing a Second Peak

04/11/23 28

Enterohepatic Recycling (Cont.)

Other compounds extensively excreted in bile include cromoglycate (unchanged drug), morphine and chloramphenicol (as glucuronide)

At least part of the biliary secretion is active since bile/plasma concentrations maybe as high as 50/1.

There can also be competition between compounds.

The efficiency of this biliary excretion system can be assessed by use of a test substance Bromsulphalein.

04/11/23 29

Pulmonary excretion

The lung is the major organ of excretion for gaseous and volatile substances.

The breathalyzer test is based on a quantitative pulmonary excretion of ethanol.

Most of the gaseous anesthetics are extensively eliminated in expired air.

04/11/23 30

Salivary excretion

Not really a method of drug excretion as the drug will usually be swallowed and reabsorbed, thus a form of ‘salivary recycling’.

Drug excretion into saliva appears to be dependent on pH partition and protein binding.

This mechanism appears attractive in terms of drug monitoring, i.e. determining drug concentration to assist in drug dosage adjustment.

For some drugs, the saliva/free plasma ratio is fairly constant such that drug concentrations in saliva could be a good indication of drug concentration in plasma.

04/11/23 31

Renal disease considerations If a drug is extensively excreted

unchanged into urine, alteration of renal function will alter the drug elimination rate.

Creatinine clearance can be used as a measure of renal function.

For most drugs which are excreted extensively as unchanged drug, a good correlationhas been found between creatinine clearance and drug clearance or observed elimination rate (since Vd is usually unchanged).

04/11/23 32

Dose adjustment Creatinine clearance

Creatinine is produced in the body by muscle metabolism from creatine phosphate.

Creatinine production is dependent on the age, weight, and sex of the patient.

Elimination of creatinine is mainly by glomerular filtration with a small percentage by active secretion.

With the patient in stable condition the production is like a continuous infusion to steady state with the infusion rate controlled by muscle metabolism and the elimination controlled by renal function.

04/11/23 33

Creatinine clearance (Cont.)

Thus as renal function is reduced, serum creatinine concentrations increases.

Other compounds such as inulin are also used for GFR measurement.

Although inulin GFR values are probably more accurate, they involve administration of inulin and careful collection of urine for inulin determination.

The major advantage of creatinine is that its formation is endogenous.

04/11/23 34

Determination of creatinine clearance

Involves collection of total urine and a plasma/serum determination at the mid-point time

04/11/23 35

Determination of creatinine clearance (Cont.)

Serum creatinine is expressed as mg/100 ml Creatinine clearance is expressed as ml/min. Normal inulin clearance values are 124 ml/min for

men and 109 ml/min for women. Because of some small renal secretion of

creatinine, normal values of creatinine clearance are slightly higher than GFR measured with inulin.

Thus, normal creatinine clearance values are about 120 to 130 ml/min.

04/11/23 36

Calculation of creatinine clearance

Equation of Cockcroft and Gault: Male:

Female:

}72

)()(140{85.0

crcr Cs

kgWeightyrAgeCl

crcr Cs

kgWeightyrAgeCl

72

)()(140