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EXCRETION OF DRUGS

A. RENAL EXCRETION MECHANISMS


I. GLOMERULAR FILTRATION
Examples of drugs eliminated by glomerular filtration: aminoglycosides, vancomycin, fluconazole
General features: prerequisites, rate determinants of GF, maximal rate achievable by GF

II. RENAL TUBULAR SECRETION


Transporters for organic anions (acids): OAT1 MRP4/OA4; examples for competitive inhibition
Transporters for organic cations (bases): OCT1 MATE1; examples for competitive inhibition
Transporters for neutral compounds (e.g. digoxin): OATP MDR1; ex. for competitive inhibition

III. RENAL TUBULAR REABSORPTION OF DRUGS


Consequence: delayed elimination
Mechanism: carrier-mediated transport (e.g. by PEPT) for some drugs; diffusion for most drugs
Influencing factors of reabsorption by diffusion:
1. Chemical factors:
a. Concentration in tubular fluid
b. The degree of ionization
- Alkalinization of tubular fluid decreases the tubular reabsorption of weak organic acids
(e.g. salicylate, phenobarbital alkalinization is used in intoxications)
- Acidification of tubular fluid decreases the tubular reabsorption weak organic bases
2. Biological factors: urine flow rate

B. BILIARY EXCRETION OF DRUGS


I. CHOLEPHILIC COMPOUNDS: relatively large (mw >500Da) amphipatic molecules
Cholephilic organic anions: endogenous comp., drugs containing a COOH group, drug conjugates
Cholephilic organic cations: quaternary N-compounds, tertiary N-compounds

II. MECHANISM OF BILIARY EXCRETION mediated by transporters


Sinusoidal uptake transporters for drugs: OATP, OCT
Bile canalicular efflux transporters for drugs: MRP2, BCRP, MDR (Pgp)

III. INTESTINAL REABSORPTION OF DRUGS Enterohepatic circulation (EHC)


Drugs undergoing EHC: glucuronides excreted in bile
Consequence of EHC: delayed elimination
Interruption of EHC: by adsorbents (cholestyramine, charcoal), inadvertently by antibiotics

C. OTHER EXCRETORY ROUTES


I. PULMONARY EXCRETION (EXHALATION)
II. GASTROINTESTINAL EXCRETION
Excretion into the stomach (amphetamine, PCP) pH entrapment in gastric acid
Excretion into the intestinal lumen
- by transporters (MDR, MRP2)
- by diffusion (extremely lipophilic chemicals)

III. GLANDULAR EXCRETION


Excretion into the milk: weak organic bases and extremely lipophilic chemicals

A. RENAL EXCRETION MECHANISMS


I. GLOMERULAR FILTRATION is the mechanism for the elimination of:
aminoglycosides, vancomycin, fluconazole, flucytosine, vigabatrin, gabapentin, topiramate, Li
GENERAL FEATURES:
Prerequisites for efficient filtration: 1. Water solubility 2. Low affinity to plasma proteins
Rate determining factors: 1. Free drug concentration in plasma 2. Glomerular Filtration Rate
Maximal renal clearance achievable: GFR (= ClKREATININE; only if PP-binding = 0, Reabs. = 0)

II. TUBULAR SECRETION mediated by transporters in the BLM and BBM


Certainly involved if the renal clearance of a drug is > GFR (= ClKREATININE)
Maximal renal clearance of a drug achievable is: RBF (= ClPAH)

For organic anions (acids):

BLOOD

R-COOH-containing compounds: PAH, penicillins,


cephalosporins, flurokinolones, NSAIDs, methotrexate

ADP

ATP
+

R-P(O)(OH)2-containing drugs: Cidofovir (against CMV)


Acidic conjugates of drugs:
Glucuronides: paracetamol-glucuronide
Sulfate-conj: paracetamol-sulfate
Glycine-conj: salicyl-glycine

Urate

Na

R-SO2NH2-containing drugs: Thiazides, furosemide

URINE

Na

-KG2-

OAT4
-KG2-

OAOAT1
ATP
MRP4

ADP
-70 mV

Competition at OAT1: Probenecid Penicillin or cidofovir; NSAID Methotrexate


Consequence: Probenecid delays the excretion of penicillin and prevents the nephrotoxicity of cidofovir.

For organic cations (bases):


Quaternary N-containing drugs:
tubocurarine, neostigmine

BLOOD

Na

URINE

ADP

ATP
+

Tertiary N-containing drugs:


metformin, quinidine, quinine, procainamide,
H2-rec. bl. (cimetidine, etc), amantadine, amiloride,
triamteren, trimethoprim, ethambutol, pindolol

Na

H
OC+
OCT2

Competition:
Trimethoprim or cimetidine Procainamide
Pyrimethamine Metformin

MATE1

-70 mV

For organic neutral compounds:


e.g. digoxin
Competition at MDR1:
Quinidine or verapamil Digoxin
Consequence:
The plasma concentration of digoxin increases
with coadministration of quinidine or verapamil.

BLOOD

ADP

ATP
+

Na

Na

Cys
GSH
Digoxin
OATP8

ATP

ADP

Another reason for increased digoxin plasma conc.:


increased digoxin absorption from the gut by inhibition of the
MDR1-mediated export of digoxin from the enterocytes
back into the gut lumen by quinidine or verapamil.

URINE

-70 mV

MDR1
(Pgp)

III. RENAL TUBULAR REABSORPTION OF DRUGS


Consequence: delayed elimination; examples:
Plasma protein binding
Glomerular filtration
Tubular reabsorption
Elimination T1/2

Gentamicin

Fluconazole

Little: 11%
Freely
MINIMAL: <2%
3 hrs

Little: <10%
Freely
EXTENSIVE: 80%
30 hrs*

*A second reason for slower elimination of fluconazol is its larger volume of distribution
(0.6 L/kg) compared to that of gentamicin (0.3 L/kg)

Another example: tubular reabsorption also slows the elimination of Li+

Li+ is freely filtered in the glomeruli, yet its renal clearance is only 10-40 ml/min, as Li+ is
largely reabsorbed in the tubules. In Li+ intoxication we can speed up the elimination of Li+ by
hemodialysis, as the hemodialysis clearance of Li+ is 70-170 ml/min.

Mechanism:
- For most drugs: diffusion
- For some -lactam antibiotics and ACE-inhibitors: PEPT-mediated

Influencing factors of reabsorption by diffusion:


1. Chemical factors:
a. Concentration in tubular fluid (increased by water reabsorption along the tubules)
b. The degree of ionization
Strong acids and strong bases are completely ionized not reabsorbed
- Acids: penicillins, drugs conjugated with glucuronic acid, sulfuric acid, or glycine
- Bases: quaternary N-containing drugs, aminoglycoside antibiotics
Weak acids and weak bases are partially ionized reabsorbed
- Acids: salicylates, phenobarbital:
ionization can be increased by alkalinization (NaHCO3 infusion)
decreased reabsorption increased urinary excretion (used in intox!)

- Bases: amfetamine, ephedrine, phencyclidine (PCP), amantadine, tocainide:


ionization can be increased by acidification (NH4Cl infusion)
decreased reabsorption increased urinary excretion
Note: Acidification would increase the urinary excretion of amphetamine and PCP,
yet it is NOT used in amphetamine and PCP intoxication see the next page for expl.

2. Biological factors:
Tubular fluid flow rate,
if high: it dilutes the drug in the tubular fluid + shortens the residence time in tubules
decreased reabsorption increased urinary excretion
Forced diuresis may be used in intoxications to increase urinary excretion of toxicants.
However, it is rarely used because of the risks of volume depletion and electrolyte imbalance.

Lower line: FORCED DIURESIS ALONE


INCREASES THE CLEARANCE OF PHENOBARBITAL SLIGHTLY.

Upper line: FORCED DIURESIS with Na-BICARBONATE INFUSION

Phenobarbital clearance (ml/min)

INCREASES THE CLEARANCE OF PHENOBARBITAL DRAMATICALLY.

alkalinization of urine
with NaHCO3 infusion

40

30

20

without NaHCO3 infusion


10

0
0

URINE FLOW (ml/min)


Alkalinization of the tubular fluid decreases the renal tubular reabsorption (and in
turn increases the urinary excretion) of weak organic acids that are at least partially
excreted unchanged in urine. Such are phenobarbital and salicylic acid. Therefore,
NaHCO3 infusion is a common therapeutic intervention in phenobarbital- or salicylateintoxicated patients. (Note: Aspirin is rapidly hydrolyzed to salicylic acid in the body.)
Acidification of the tubular fluid, in contrast, is a procedure to decrease the renal
tubular reabsorption and in turn to increase the urinary excretion of weak organic
bases, such as amantadine, in intoxicated patients. This procedure, however, is not
used if the organic base is convulsive, such as amphetamine and phencyclidine (PCP).
In convulsion, muscle injury (rhabdomyolysis) may occur with myoglobinuria, and
myoglobin is prone to precipitate in the acidic tubular fluid, causing renal failure.
Note: Neither of these procedures is applicable to enhance the urinary excretion of
drugs that are excreted only as metabolites (e.g. tricyclic antidepressants).
These are not eliminated by excretion, but by biotransformation!

B. BILIARY EXCRETION OF DRUGS


I. Cholephilic compounds
1. General properties: - are relatively large molecules (m.w. >500 Da)
- are amphipatic molecules
Small m.w. organic acids (<500 D) are excreted by the kidneys into urine,
Large m.w. amphipatic organic acids (>500 D) are transported into bile.

Excreted by
renal tubular secretion

Excreted by
hepatobiliary transport

COOH

H2 C

CH2

CH3

CH 3

CH3

N
H

Benzylpenicillin
(Penicillin G)
m.w. 334

N
N

Cefoperazone
m.w. 646
COOH

O
C

O
H

HO

C
H

N
H

CH3
N

CH 2 S

N
S

HN

O
C

COOH

N
H

CH2 COOH
Cl

OH

Salicyl-glycine
(Salicyluric acid)
m.w. 165

Montelukast
m.w. 586

H3C
H3C

CH3

2. Examples for
Cholephilic organic anions
Cholephilic organic cations
Endogenous compounds:
Bile acids (as taurine or glycine conjugates)
Bilirubin (as mono- and diglucuronide)
Steroid hormones (as glucuronides)
Thyroxine (as glucuronide)

Drugs containing COOH group:


Some cephalosporins: cephoperazone,
cephtriaxone
Some ACE inhibitors: fosinopril, spirapril
Others: statins, fexofenadine,
montelukast, chromoglycate,
cholecystographic contrast agents

Drugs conjugated with


- Glucuronic acid: digitoxin, ezetimibe,
phenolphthalein,
indomethacin, telmisartan
carbamazepine, dapsone

- Glutathione: sulfobromophthaleine (BSP)

Quaternary N-containing drugs:


Vecuronium

Tertiary N-containing drugs:


Rifampin, erythromycin, doxycycline,
vincristine, vinblastine, cyclosporine

II. Mechanism of biliary excretion mediated by transporters

MRP2 substrates may also be transported into bile by BCRP, another primary active transporter in the bile canalicular membrane of hepatocytes.

The chemical property of the glucuronide formed in the liver determines which
transporter exports it from the liver cell: MRP1 into blood, or MRP2 into bile.
After formed in the liver, chloramphenicol glucuronide (mw 498) is transported into blood via MRP1
and MRP3 and then it is excreted into urine, whereas the larger ezetimibe glucuronide (mw 583; see
elsewhere) and bilirubin diglucuronide (mw 934) are transported into the bile via MRP2.
Chloramphenicol

Chloramphenicol glucuronide
(m.w. 498)

OH
O2N

OH
UDP-GT
UDP-GA

CH CH CH2 OH

O 2N

CH CH CH2 O
NH

H 3C

CH

H
N

H3C
CH2 CH

HO

H
N

CH2

CH2

CH2

CH2

CH2

C
O

C CHCl2

OH

CH

BLOOD

URINE

Bilirubin diglucuronide (m.w. 934)

Bilirubin (not excreted)


H
N

HO OH

Mrp1,3

C CHCl2

NH

COO

H
N

CH
CH 3

CH

H
N

H
N

CH2

H
N

CH

UDP-GT
UDP-GA

CH3

H
N

CH2

H 3C

H 3C
CH2 CH

OOC

OH

O
O

OH

CH2

CH 2

CH2

CH2

C
O

CH 3

CH

CH3

COO

HO

HO

OH
HO

OH

Mrp2

BILE

CH2

III. INTESTINAL REABSORPTION OF DRUGS


Enterohepatic circulation (EHC)
Drugs undergoing EHC:
Typically, drugs that are excreted in bile as glucuronides (see above) undergo EHC.
The intestinal microflora produces -glucuronidase enzyme
hydrolysis of the highly water-soluble glucoronide in the colon
release of the relatively lipophilic aglycone
reabsorption of the aglycone (i.e., the parent drug) into the portal blood

Consequence of EHC: delayed elimination and prolonged action


Examples:
Dapsone BILE, as dapsone-N-glucuronide, T1/2 = 1 day
Carbamazepine BILE, as carbamazepine-N-glucuronide, T1/2 = 1-3 days
Digitoxin BILE, as digitoxigenin-monodigitoxoside-glucuronide, T1/2 = 7 days
Note, that digitoxin is excreted into bile as the glucuronide via the canalicular MRP2 transporter,
whereas digoxin is excreted unchanged into urine by tubular secretion via the luminal MDR1
transporter or Pgp (see above).

Interruption of EHC (by preventing reabsorption):


facilitates elimination of the drug by fecal excretion
Intentional interruption of EHC:
Aim:
to promote elimination of a drug in drug overdose
Method: by oral administration of non-absorbable adsorbents, such as
- Cholestyramine: in digitoxin intoxication
- Charcoal:
in intoxications with
- carbamazepine
- dapsone

Inadvertent interruption of EHC:


May be caused by antibiotics that eradicate the colonic microflora.
Consequence: decreased hydrolysis of the glucuronide by -glucuronidase
into the relatively lipophilic parent drug (aglycone)
decreased reabsorption of the drug into the portal blood
Example:
Doxycyclin (DC) may cause contraceptive failure in women who take
contraceptives containing estrogens (which are excreted into bile as glucuronides)
Therapy with DC (a broad spectrum antibiotic)
the number of colonic bacteria
-glucuronidase activity in the gut lumen
hydrolysis of estrogen-glucuronides
reabsorption of estrogens, increased fecal excretion
Contraceptive failure and unwanted pregnancy

C. OTHER EXCRETORY ROUTES


I. PULMONARY EXCRETION (EXHALATION)
Volatile compounds: - gases (N2O, toxic gases)
- volatile liquids (inhalation anesthetics, solvents)
Mechanism: diffusion, driven by the blood-alveolar partial pressure gradient
delayed by high solubility in blood or tissues (e.g. N2O vs. halothane)

II. GASTROINTESTINAL EXCRETION


Excretion into the stomach: lipid-soluble weak organic bases
Examples: amphetamine, phencyclidine (PCP), methadone
Mechanism: diffusion from the blood into the stomach (HCl)
protonation into positively charged cation, which cannot diffuse back to blood
= pH-entrapment of the drug in the gastric acid
Note: Drugs entrapped in the gastric acid can be reabsorbed from the intestinal tract,
unless that is prevented by aspiration of the gastric juice. Aspiration of the gastric juice is a
procedure used in amphetamine and PCP intoxication to increase elimination these drugs.

Excretion into the intestinal lumen:


1. By carriermediated transport by transporters (exporters) in the BBM of enterocytes:
- Substrates of P-gp = MDR1 (digoxin, vinca alkaloids, ivermectin, etc.)
Export into the intestinal lumen by P-gp cause low bioavailability of the P-gp-substrate drugs
when given orally, and may contribute to their elimination when given parenterally.
- Substrates of MRP-2 (organic acids; significance still requires definition)
2. By diffusion: extremely lipophilic compounds (these are not drugs!)
e.g. TCDD (dioxin): The intestinal excretion of TCDD is facilitated by an apolar non-absorbable
substance in the gut lumen in which TCDD is dissolved and retained, such as olestra, a nonabsorbable fat-substitute used in chips. Olestra has been used to facilitate intestinal and fecal
excretion of TCDD in humans intoxicated with dioxin. (The T1/2 of TCDD is 7 years; after
prolonged oral treatment with olestra it decreased to 1.5 years.)
+

3. By the K+ secretion mechanism in the colon: Tl (Thallium sulfate is a rodenticide.)


Tl+ thus secreted can be trapped by Berliner blue given orally in Tl-intoxication.
Berliner blue = KFe[Fe(CN)6] = potassium-ferri-hexa-cyanoferrate (complexes K+ or Tl+ ions)

Tl+

KFe[Fe(CN)6]

TlFe[Fe(CN)6] + K+

III. GLANDULAR EXCRETION


Excretion by the mammary gland (via the milk):
1. Weak organic bases: by diffusion and pH-entrapment (milk pH=7.0, more acidic than plasma)
e.g.: amphetamine, morphine, heroin
These drugs may be transferred via the milk from the lactating mother into the suckling baby.
2. Extremely lipophilic compounds (not drugs): by diffusion and entrapment in milk fat
e.g.: TCDD (dioxin) and polychlorinated biphenyls (PCBs)
Contamination of the cow milk in grazing areas polluted with such extremely lipid-soluble
environmental chemicals (e.g., PCBs) has occurred and it is still of concern.