Download Part 7. EXCRETION OF DRUGS ELIMINATION MECHANISMS

Part 7. EXCRETION OF DRUGS
A. INTRODUCTION
I. EXCRETION – contribution of excretion to elimination of drugs (with examples)
II. THE ROUTES OF EXCRETION
B. REN AL EXCRETION OF DRUGS
I. STRUCTURAL FEATURES – the nephron: the glomerulus and the tubular system
II. GLOMERULAR FILTRATION (GF) – Examples of drugs eliminated by GF; General features of GF
III. RENAL TUBULAR SECRETION
Transporters for organic anions (acids): OAT1  MRP4/OAT4; 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
IV. 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. phenobarbital, salicylate – alkalinization is used in intoxications
- Acidification of tubular fluid decreases the tubular reabsorption weak organic bases
2. Biological factors: the urine flow rate
C. BILI ARY EX CRETION OF DRUGS
I. STRUCTURAL FEATURES – the hepatic lobule and sinusoid
II. CHOLEPHILIC COMPOUNDS: relatively large (mw >500Da) amphipathic molecules
1. General properties of cholephilic compounds
2. Cholephilic organic anions: endogen. comp., drugs containing COOH group, drug conjugates
Cholephilic organic cations: quaternary N-compounds, tertiary N-compounds
III. MECHANISM OF BILIARY EXCRETION – mediated by transporters
1. Sinusoidal uptake transporters for drugs: OATP, OCT1, OAT2
2. Bile canalicular efflux transporters for drugs: MRP2, BCRP, MDR (Pgp)
3. Sinusoidal (basolateral) efflux transporters for drugs: MRP1, MRP3-6
IV. INTESTINAL REABSORPTION OF DRUGS – Enterohepatic circulation (EHC)
1. Drugs undergoing EHC: glucuronides excreted in bile (telmisartan, dapsone, digitoxin)
2. Consequence of EHC: delayed elimination
3. Interruption of EHC: by adsorbents (cholestyramine, charcoal), inadvertently by antibiotics
V. WHY IS IT USEFUL TO KNOW THAT A DRUG IS ELIMINATED BY BILIARY EXCRETION?
D. OTHER EXCRETORY ROUTES
I. PULMONARY EXCRETION (EXHALATION)
II. GLANDULAR EXCRETION
Excretion into the milk (weak organic bases and highly lipophilic chemicals), saliva, and sweat
III. GASTROINTESTINAL EXCRETION
1. Excretion into the stomach (amphetamine, PCP) – pH entrapment in gastric acid
2. Excretion into the intestinal lumen
a. By diffusion, promoted by a non-absorbable binding substance in the lumen
e.g., by charcoal: phenobarbital and others; by olestra: TCDD
b. By transporters (MDR1, MRP2)
c. By the K+ secretion mechanism in the colon – fecal Tl+ excretion is promoted by Berliner blue
E. APPENDIX: 1. Antipyrine elimination as measured by decline in the salivary concentration of antipyrine. 2.
Why can we increase the urinary excretion of phenobarbital by alkalinization of the renal tubular fluid? 3. Why
does water-solubility promote and lipid-solubility retard the excretion of compounds? What is biomagnification?
Why did the falcons of Long Island die?
A. INTRODUCTION
I. EXCRETION – Its contribution to elimination of drugs (with examples)
Drugs may be eliminated by excretion and/or biotransformation:
ELIMINATION MECHANISMS
Physical mechanism:
Chemical mechanism:
EXCRETION
BIOTRANSFORMATION
CONTRIBUTION OF EXCRETION AND BIOTRANSFORMATION
TO ELIMINATION OF DRUGS  Examples
DRUGS ELIMINATED BY
EXCRETION,
i.e.
NOT biotransformed
and excreted as parent drugs
(in unchanged form)
DRUGS ELIMINATED BY
BIOTRANSFORMATION,
i.e.
fully biotransformed, and
excreted only as metabolites
Benzylpenicilin
Aminoglycosides
Metformin
Tubocurarine
Amantadine
form several metabolites
DRUGS ELIMINATED BY
BOTH BIOTRANSFORMATION
AND EXCRETION,
i.e.
excreted both as parent drugs
and as metabolites
TCADs
Phenothiazines
form several metabolites
Chloramphenicol
forms one main metabolite,
the glucuronic acid conjugate
Salicylates
Paracetamol
(Acetaminophen)
Phenobarbital
NOTE: Both the drug (the parent compound) and its metabolites can be excreted.
However, excretion of the drug is an elimination mechanism for the drug, whereas
excretion of the metabolite is NOT. Excretion of the metabolite is an elimination
mechanism for the metabolite only, not for the parent compound, because the parent
compound is eliminated at the moment it is converted into a metabolite.
II. THE ROUTES OF EXCRETION (excretory organs)
1. RENAL (URINARY) EXCRETION – by two mechanisms:
- Glomerular filtration, and/or
- Tubular secretion – carrier-mediated transport
Renal excretion can be counteracted by tubular reabsorption.
2. BILIARY EXCRETION – by carrier-mediated trp. (followed by fecal excretion)
Fecal excretion can be counteracted by intestinal reabsorption.
3. OTHER ROUTES
- Pulmonary excretion (exhalation)
- Glandular excretion via the milk, saliva, sweat
- Gastrointestinal excretion
B. RENAL EXCRETION OF DRUGS
I. STRUCTURAL FEATURES – Nephron: the glomerulus and the tubules
II. RENAL TUBULAR SECRETION OF DRUGS
 Direction: From the renal peritubular capillaries (containing fenestrated endothelial cells),
through the proximal tubular cells (PTC) into the tubular lumen.
 Tubular secretion is certainly involved in the renal excretion of a drug if the renal clearance of
the drug is larger than the GFR  ClCREATININE  100 mL/min. However, if the renal Cl of a drug is
<100 mL, it may still be filtered and/or secreted, but then it is also reabsorbed from the tubules.
 The highest renal clearance of a drug (if secreted) achievable = RPF = ClPAH = 600 mL/min
 Mechanism of tubular secretion: carrier-mediated transport
- Transporters are located in both the basolateral membrane (facing the blood) and
the apical membrane (facing the tubular fluid) of the PTC.
- Transport systems work for secretion of organic anions, cations and neutral compounds
(with often overlapping substrate specificities).
FOR ORGANIC ANIONS (acids), e.g.:
BLOOD
 R-COOH-containing compounds: PAH, penicillins,
cephalosporins, fluroquinolones, NSAIDs, methotrexate
 R-SO2NH2-containing drugs: Thiazides, furosemide
 R-P(O)(OH)2-containing drugs: Cidofovir (against CMV)
 Acidic conjugates of drugs:
Glucuronides:
paracetamol-glucuronide
Sulfate-conjugates: paracetamol-sulfate
Glycine-conjugates: salicyl-glycine
Scheme of the nephron with the glomerulus,
the tubular system, and its microcirculation.
Tubular secretion of drugs takes place in the
proximal tubules, whereas reabsorption of drugs
by diffusion may occur all along the tubules. As
drugs become more and more concentrated in
the tubular fluid as they move along the tubules,
the driving force for diffusion of drugs back from
the tubules increases in the distal nephron.
K
ADP
ATP
Na
URINE
+
+
Urate
+
Na
-KG2-
OAT4
-KG2-
OAOAT1
ATP
MRP4
ADP
-70 mV
Competition for OAT1 – Examples:
Probenecid  Penicillin; Probenecid  Cidofovir; NSAIDs  Methotrexate
Consequence: Probenecid delays the excretion of penicillin and prevents the nephrotoxicity of cidofovir.
A. Scheme of the glomerular capillaries.
B. Cross-section of the glomerular capillary
membrane through which filtration of drugs
takes place: the capillary endothelium, the
basement membrane, and the epithelium with
podocytes.
II. GLOMERULAR FILTRATION (GF)
1. DRUGS ELIMINATED BY RENAL EXCRETION WITH GF AS THE MAIN MECHANISM:
aminoglycosides, vancomycin, fluconazole, flucytosine, vigabatrin, gabapentin, topiramate, Li+, etc.
2. GENERAL FEATURES:
a. Prerequisites for efficient glomerular filtration of a drug:
 Water solubility
 Not too large size (cutoff for glomerular filtration is ~ 60 kDa)
 Low plasma protein binding (PPB)
b. Rate-determining factors of glomerular filtration of a drug:
 The free drug concentration in plasma – filtration is a conc.-dependent, 1st-order elimination
 The glomerular filtration rate (GFR) – if the GFR decreases (in neonates, or renal disease)
the elimination T1/2 of drugs cleared by filtration becomes proportionately prolonged.
c. The highest renal clearance of a drug achievable by GF alone = GFR = 100 mL/min
(GFR  ClCREATININE); only if both the PPB and the tubular reabsorption of the drug is ~0.
FOR ORGANIC CATIONS (bases), e.g.:
BLOOD
 Quaternary N-containing drugs:
tubocurarine, neostigmine
 Tertiary N-containing drugs (in protonated form):
metformin,
quinidine,
quinine,
procainamide,
H2-rec. bl. (cimetidine, etc.), amantadine, amiloride,
triamterene, trimethoprim, ethambutol, pindolol
Competition for MDR1 (Pgp):
Quinidine or verapamil  Digoxin
Consequence:
The plasma concentration of digoxin
increases with coadministration of quinidine or verapamil.
+
URINE
+
Na
H
+
H
OC+
OCT2
+
MATE1
-70 mV
BLOOD
URINE
+
K
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.
Na
ADP
ATP
Competition – Examples:
Trimethoprim or cimetidine  Procainamide
Pyrimethamine  Metformin
FOR ORGANIC NEUTRAL
COMPOUNDS, e.g. digoxin
+
K
-70 mV
MDR1
(Pgp)
II. RENAL TUBULAR REABSORPTION OF DRUGS
1. Consequences of tubular reabsorption of drugs:
decreased renal clearance and delayed elimination
Example-1: - Gentamicin (an aminoglycoside antibiotic, which is not reabsorbed)
- Fluconazole (a systemic antimycotic drug, which is reabsorbed)
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 salicylate (e.g. aspirin)-intoxicated patients.
NOTE: Aspirin rapidly hydrolyzes to salicylic acid in the body. In aspirin overdose, salicylic acid is
largely responsible for the toxicity, as it is a mitochondrial uncoupler and coenzyme A-depletor.
Remember: In addition to urinary excretion, salicylic acid is also eliminated by glycine conjugation.
Gentamicin
Fluconazole
Little: 11%
Little: <10%
Freely
Freely
MINIMAL: <2%
EXTENSIVE: 80%
90 mL/min
18 mL/min
3 hrs
30 hrs*
*A second reason for slower elimination of fluconazole is its larger volume of distribution (0.6 L/kg) as
compared to that of gentamicin (0.3 L/kg).
FIGURE:
An experiment on dogs.
Upper line:
Plasma protein binding
Glomerular filtration
Tubular reabsorption
Renal clearance
Elimination T1/2
Forced diuresis together with Nabicarbonate infusion increases the
clearance of phenobarbital dramatically.
Example-2: The tubular reabsorption slows the elimination of lithium. Li+ is freely filtered
Lower line:
in the glomeruli, yet its renal clearance is only 10-40 mL/min, i.e. much less than the GFR (100
mL/min). This is because Li+ is largely reabsorbed in the tubules. In Li+ intoxication the elimination of
Li+ can be accelerated by hemodialysis, as the hemodialysis clearance of Li+ is 70-170 ml/min.
Forced diuresis alone increases the
clearance of phenobarbital slightly.
2. Mechanism of the tubular reabsorption of drugs:
 For most drugs: diffusion
 For some β-lactam antibiotics and ACE-inhibitors: PEPT-mediated
3. Factors influencing the reabsorption of drugs by diffusion:
a. Chemical factors:
i. The concentration in tubular fluid (increased by water reabsorption along the tubules)
ii. The degree of ionization (calculated by means of the H-H equation – see Appendix 3)
 Strong acids and strong bases are completely ionized → not reabsorbed
- Acids: penicillins, drugs conjugated with glucuronic acid, sulfate, or glycine
- Bases: quaternary N-containing drugs, aminoglycoside antibiotics (which are polycations)
Why alkalinization by NaHCO3 infusion decreases the renal tubular reabsorption of
phenobarbital and salicylic acid? In the alkaline tubular fluid with the rise in pH phenobarbital is
increasingly deprotonated, thus acquiring a negative charge. Therefore, the proportion of uncharged
molecules that is lipid-soluble and can be reabsorbed by diffusion decreases. The mechanism
whereby NaHCO3 infusion facilitates urinary excretion of salicylic acid (whose pK=3 and thus is
almost completely anionic at the normal pH of urine) is unknown (see Appendix 2 for more detail).
FORM
Phenobarbital pKa=7.2
Salicylic acid pKa=3
UNCHARGED FORM
Formed in ACIDIC tub fluid
Lipid-soluble
Diffusible across membranes
REABSORBED
O
H5C2
Phe
O
NOTE: Acidification would increase the urinary excretion of amphetamine and phencyclidine
(PCP), yet it is CONTRAINDICATED these intoxications – see the next page for explanation.
b. Biological factors: The tubular fluid flow rate (TFR)
High TFR dilutes the drug in the tubular fluid + shortens its residence time in tubules, therefore
high TFR decreases the reabsorption and increases the urinary excretion of the drug.
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.
+
O
CHARGED (ANIONIC) FORM
H5C2
C
N
H
OH
OH
H
H
Formed in ALKALINE tub fluid
NOT lipid-soluble
NOT diffusible across membranes
NOT REABSORBED
O
O
 Weak acids and weak bases are partially ionized → the non-ionized form is reabsorbed
- Acids, e.g. phenobarbital (see also next page and Appendix 2):
They become increasingly deprotonated into an anionic form by alkalinization (NaHCO3), thus
the proportion of their non-ionized form is decreased → decreased reabsorption → increased
urinary excretion (NaHCO3 is infused to phenobarbital- and salicylate-intoxicated patient)
- Bases, e.g. amphetamine, ephedrine, PCP, amantadine, meperidine (pethidine), tocainide:
They become increasingly protonated into a cationic form by acidification (NH4Cl dosing),
thus the proportion of their non-ionized form is decreased →  reabsorption → increased
urinary excretion.
O
H
N
+
H
+
H
+
H
N
O
O
Phe
C
N_
O
O_
OH
ACIDIFICATION of the tubular fluid by NH4Cl administration, 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. These drugs are tertiary amines which are
protonated in the acidic tubular fluid, thus acquiring a positive charge. 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, which may result in myoglobinuria. Myoglobin
may precipitate in the acidic tubular fluid, causing renal failure.
NOTE: Neither of these procedures is applicable to enhance the urinary excretion of drugs which are
excreted only as metabolites (e.g. tricyclic antidepressants), as these are not eliminated by excretion,
but by biotransformation, or which are not reabsorbed (e.g. strong acids or bases).
C. BILIARY EXCRETION OF DRUGS
I. STRUCTURAL FEATURES
– the liver lobule, the sinusoids and the bile canaliculi
FIGURES:
1: The cross section of the
hepatic lobule.
2. The hepatic sinusoids
Note, that the mixed blood from the
terminal branches of the portal vein and
hepatic artery flows in the hepatic
sinusoids from the periphery of the
lobule into the central vein.
The membrane domain of the liver cells
(hepatocytes) that faces the sinusoids is
called sinusoidal membrane. This
contains microvilli (to increase the
surface area) and is packed with
membrane transporters (to import
compounds from the blood into the
hepatocytes and export others from the
hepatocytes into the blood). Uptake of
drugs from the hepatic sinusoids is also
assisted by the fenestrae of sinusoidal
endothelial cells and the lack of
basement membrane. The fenestrae
permit the passage of even proteinbound drugs out from the blood into an
extracellular space (called the space of
Disse) between the endothelium and the
sinusoidal membrane of hepatocytes.
Hepatocytes facing each other enclose
an extracellular space which forms the
bile canaliculi in between rows of liver
cells, and which is sealed by tight
junctions between the liver cells. So bile
canaliculi are lined by a membrane domain of adjacent liver cells, called the bile canalicular
membrane. This is also specialized for transport because it contains microvilli and several
transporters, typically primary active ATP-using transporters, most notably MRP2 and BSEP (bile salt
export pump). These ABC transporters work as exporters, and pump compounds out from the
hepatocyte into the bile canaliculi. For example, MRP2 pumps cholephilic organic acids into bile (e.g.
cefoperazone, and bilirubin-monoglucuronide and -diglucuronide) and BSEP exports taurine- and
glycine-conjugated bile acids. Bile canaliculi have dead ends close to the central vein, and they run
between adjacent liver cells toward the periphery of the lobule where they carry the bile into the bile
duct. Thus, blood and bile flow in opposite directions in the hepatic lobules.
II. CHOLEPHILIC COMPOUNDS
Compounds that are preferentially excreted in bile rather than in urine are called cholephilic.
1. Cholephilic compounds – general properties
 relatively large molecules (m.w. >500 Da)
 amphipathic molecules
Amphipatic (or amphiphilic) molecule = one part of the molecule has apolar lipophilic properties,
whereas the other part is polar (often charged) and hydrophilic (for example, bile acids).
In general, SMALL organic acids (m.w. <500 D) are excreted by the kidneys into
urine, whereas LARGE amphipathic organic acids (m.w. >500 D) are transported
into bile. Examples:
CH3
COOH
O
N
O
H2C
C
S
N
H
CH2
CH3
O
N
O
N
Cefoperazone
m.w. 646
CH3
Benzylpenicillin
(Penicillin G)
m.w. 334
N
COOH
O
C
O
H
HO
C
H
C
N
H
CH3
N
CH2 S
N
N
S
HN
O
N
O
C
N
H
OH
Salicyl-glycine
(Salicyluric acid)
m.w. 165
COOH
S
CH2 COOH
Cl
N
Montelukast
m.w. 586
Excreted mainly by
renal tubular secretion
H3C
H3C
CH3
Excreted mainly by
hepatobiliary transport
2. Cholephilic compounds – Examples
 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
Organic
anions
(acids)
Some cephalosporins: cefoperazone, ceftriaxone
Some ACE inhibitors: fosinopril, spirapril
Others:
statins, fexofenadine, montelukast, cromoglycate, valsartan,
cholecystographic contrast agents
 Drugs conjugated with
- Glucuronic acid: digitoxin, ezetimibe, phenolphthalein, indomethacin, telmisartan,
mycophenolic acid, carbamazepine, dapsone
- Glutathione:
sulfobromophthaleine (BSP)
Organic
cations
(bases)
 Quaternary N-containing drugs: vecuronium (largely), rocuronium (partly)
 Tertiary N-containing drugs:
Rifampicin, erythromycin, doxycycline, vincristine, vinblastine, cyclosporine
III. Mechanism of biliary excretion – carrier-mediated transport
hepatic
sinusoid
BLOOD
hepatic
sinusoid
BLOOD
MRP1
MRP3
MRP4
MRP5
MRP6
OATP1A2
BSEP
NTCP
OCT1
MDR1
OAT2
MRP2
OATP1B1
BCRP
OATP1B3
BILE
MDR3
HEPATOCYTE
OATP2B1
HEPATOCYTE
UPTAKE transporters
moving drugs INTO LIVER
EFFLUX transporters
moving drugs INTO BILE
EFFLUX transporters
moving drugs INTO BLOOD
secondary/tertiary active transporters
primary active transporters
primary active transporters
OATP
OAT
organic aniontransporting polypeptide
organic anion transporter
MRP2
BCRP
OCT
organic cation transporter MDR1
NTCP
sodium taurocholate
transporting polypeptide
MDR3
BSEP
multidrug resistanceassociated protein 2
breast cancer resistance
protein (a half transporter)
multidrug resistance
protein 1 (P-glycoprotein)
multidrug resistance
protein 3 (phosphatidylcholine translocase)
bile salt export pump
MRP1
MRP3
MRP4
multidrug
resistanceassociated
MRP5
proteins
MRP6
Biliary excretion of drugs may involve 3 steps - see examples in the table below
 Uptake into the hepatocyte across the sinusoidal membrane – by diffusion and/or transporters
 Biotransformation into a cholephilic metabolite – unnecessary if the parent drug is cholephilic
(e.g. cefoperazone, telmisartan). Often a compound obtains cholephilic property (i.e. size > 500Da
and amphiphilicity) by forming a conjugate with glucuronic acid (e.g. bilirubin, ezetimibe, digitoxin).
 Export into the bile canaliculus across the canalicular membrane – by ABC transporters
Hepatic uptake
Hepatobiliary
Compound
Biotransformation
Form in bile
mechanism
exporter
Cholic acid
Bilirubin (Bi)
Cefoperazone
Fexofenadine
Valsartan
Telmisartan
Ezetimibe
NTCP + OATP
Diffusion + OATP
OATP1B1, 1B3
OATP1B1, 1B3
OATP1B1, 1B3
OATP1B3
Diffusion + OATP?
Simvastatin,
pravastatin
OATP1B1
Montelukast
Doxorubicin
Rifampicin
OATP2B1
Diffusion + OATP?
Diffusion + OATP?
Vinblastine
Diffusion + OATP?
Cyclosporin A Diffusion + OATP?
Conj. with glycine or taurine
Conj. with glucuronic acid
None
None
None
Conj. with glucuronic acid
Conj. with glucuronic acid
Lactone ring hydrolysis by
PON, hydroxylation and
dehydrogenation by CYP3A4
BSEP
MRP2
MRP2, BCRP
MRP2, MDR1
MRP2
MRP2
MRP2
Conjugated CA
Bi-glucuronides
Parent compound
Parent compound
Parent compound
Telmisartan-glucur.*
Ezetimibe-glucur.*
MRP2, BCRP
Parent + metabolites
CYPs
Carbonyl reduction
Hydrolysis (deacetylation)
Hydrolysis (deacetylation)
+ others
MRP2
MDR1
MDR1
Metabolites mainly
Parent + metabolite
Parent + metabolite
MDR1
Metabolites
Hydroxylations by CYP3A4
MDR1
Metabolites
* The biliary excretion of glucuronides leads to enterohepatic circulation of drugs (see below).
Often a drug taken up by the liver is not excreted into bile, but is exported back into
the sinusoidal blood. These drugs apparently are not good substrates for the canalicular
transporters (e.g. MRP2), but are good substrates for the basolateral transporters (e.g.MRP4), which
exports them back into the blood. This is the case, for example, for methotrexate and metformin,
which are eventually eliminated from the body largely by urinary excretion. Yet, uptake of metformin
(an antidiabetic drug) into the liver (by OCT1) is important for its pharmacological effect (inhibition of
gluconeogenesis) and its adverse effect (induction of lactic acidosis).
Often a glucuronic acid conjugate formed in the liver is not excreted into bile, but is
exported back into the sinusoidal blood. Such are, for example, the glucuronides of
paracetamol, propofol, chloramphenicol, valproic acid, and fibrate esters, e.g. fenofibrate. After
uptake into the liver, paracetamol, propofol, and chloramphenicol are directly conjugated with
glucuronic acid on their -OH group, whereas valproic acid is glucuronidated on its -COOH group.
However, fenofibrate is first hydrolyzed by carboxylesterases to fenofibric acid, which is then
conjugated with glucuronic acid on its -COOH group. These glucuronides are apparently not good
substrates for the canalicular transporters (e.g. MRP2, BCRP), but are good substrates for the
basolateral transporters (MRP1, MRP3-6), which export them back into the blood. These conjugates,
such as propofol glucuronide (see figure below), are eventually excreted into urine.
In contrast, the larger molecular weight amphipatic glucuronides of bilirubin (see figure below),
telmisartan, digitoxin, and ezetimibe are delivered into bile by MRP2 located in the canalicular
membrane. The biliary excretion of such glucuronides leads to enterohepatic circulation of drugs (see
next page), which prolongs their elimination from the body.
FIGURE: The chemical property of the glucuronide formed in the liver
determines which transporter exports it from the liver cell – MRP1 and MRP3-6
into blood, whereas MRP2 into bile.
After being formed in the liver, the relatively LARGE ezetimibe glucuronide (m.w. 583), telmisartan
glucuronide (m.w. 691), and bilirubin diglucuronide (m.w. 934; see figure) are transported into the
bile via MRP2. In contrast, the SMALLER glucuronides of valproic acid (m.w. 320), propofol (m.w.
354, see the figure below), paracetamol (m.w. 326), and chloramphenicol (m.w. 498) are
transported into blood via MRP1 and/or MRP3-6 and eventually are excreted into urine.
Bilirubin diglucuronide (m.w. 934)
Bilirubin (not excreted)
O
H 3C
H
N
CH
H
N
H 3C
CH2 CH
CH2
CH2
CH2
CH2
CH2
C
HO
H
N
CH
H
N
O
UGT
UDP-GA
CH3
CH
CH3
CH2
O
H3C
_
C
O
H
N
O
H
N
CH
H3C
CH2 CH
OOC
O
H
N
CH2
CH2
CH2
CH2
CH2
O
OH
CH3
CH
CH3
O
O
COO
CH2
_
C
C
OH
H
N
CH
O
O
O
HO
HO
OH
HO
OH
MRP2
BILE
_
COO
Propofolol
I.v. general
anesthetic
O
UGT
OH
UDP-GA
O
HO
OH
Propofol
glucuronide
(m.w. 354)
OH
MRP1,3,4
BLOOD
URINE
Mutation in the human gene coding for the bile canalicular MRP2 transporter causes the DubinJohnson syndrome, a hyperbilirubinemia with retention of conjugated bilirubin in the blood.
IV. INTESTINAL REABSORPTION OF DRUGS – Enterohepatic
circulation (EHC) of drugs
Drugs/metabolites excreted in bile are not necessarily
cleared from the body by fecal excretion because they
may be reabsorbed from the gut, at least in part.
1. Drugs undergoing EHC:
a. Drugs excreted in bile as glucuronides undergo EHC.
MECHANISM: The intestinal bacteria produce β-glucuronidase
enzyme  in the colon, β-glucuronidase can hydrolyze the
highly water-soluble glucuronic acid conjugate into glucuronic
acid and the aglycone (often an active drug)  the relatively
lipophilic aglycone released from the conjugate is reabsorbed
into the portal blood and returns to the liver. There it may be
taken up, glucuronidated and transported into bile again (thereby
completing an EHC). Alternatively, the aglycone escapes hepatic
uptake (at least in part), enters the systemic circulation and is
excreted into urine (see the scheme). Thus, glucuronidation,
when followed by biliary excretion, is a reversible elimination!
b. Drugs excreted in bile in forms absorbable from the gut can also undergo EHC.
For example, rifampin (an orally used antibiotic) is excreted in bile partly in unchanged form (which
is reabsorbed and undergoes EHC), partly in a deacetylated form (which is poorly absorbed).
In contrast, drugs excreted in bile in a form that is not absorbed from the gut do NOT undergo EHC.
Such are (a) the antibiotic cefoperazone and ceftriaxone (which are carboxylic acids, excreted in
unchanged form, not absorbed from the gut; given only i.v.), (b) the muscle relaxant vecuronium and
rocuronium (which are quaternary amines, not absorbed, and given only i.v.), and (c) doxorubicin
(which is returned by MDR1 = Pgp from the enterocytes into the gut, and given only i.v.).
2. Possible consequences of EHC – if drugs are returned partly into the systemic blood:
a. Delayed elimination, i.e. relatively long plasma T 1/2, and prolonged action. Examples:
 Telmisartan: excreted in bile as telmisartan ester-glucuronide, T1/2 = 1 day
 Dapsone: excreted in bile as dapsone N-glucuronide, T1/2 = 1 day
 Carbamazepine: excreted in bile as carbamazepine N-glucuronide, T1/2 = 1-3 days
 Digitoxin: excreted in bile as digitoxigenin-monodigitoxoside glucuronide, T1/2 = 7 days
NOTE: Digitoxin is excreted in bile as a glucuronide via the MRP2 transporter, whereas digoxin
is excreted unchanged in urine by tubular secretion via the luminal MDR1 (Pgp) transporter.
b. If the EHC returns a large quantity of the drug into the systemic circulation, a
second peak in the plasma concentration versus time curve of the drug may appear a
few hours after dosing.
3. Interruption of EHC (by preventing reabsorption) facilitates the elimination of
drugs by fecal excretion
a. Intentional interruption of EHC
• Aim:
to promote elimination of a drug after overdose
• Method: by oral administration of a non-absorbable resin or adsorbent, such as
- Cholestyramine: in digitoxin intoxication
- Charcoal:
in intoxications with carbamazepine or dapsone
The adsorbents bind the glucuronide and/or the released aglycone and thus prevent reabsorption
of the active drug from the gut. The adsorbed drug/glucuronide is excreted into feces.
b. Inadvertent interruption of EHC
• May be caused by antibiotics which alter the colonic microflora.
• Consequence: decreased hydrolysis of the glucuronide by β-glucuronidase into the relatively
lipophilic parent drug (aglycone)  decreased reabsorption of the drug
EXAMPLE: Doxycycline (DC) may cause contraceptive failure in women who take contraceptives
containing estrogens, e.g. ethinyl estradiol, which is excreted into bile as the glucuronide.
MECHANISM:
Therapy with DC (a broad spectrum antibiotic)
  the number of colonic bacteria
  β-glucuronidase activity in the colon
  hydrolysis of estrogen glucuronides (e.g. ethinyl-estradiol glucuronide)
  reabsorption and increased fecal excretion of the estrogen (e.g. ethinyl-estradiol)
 Contraceptive failure and unwanted pregnancy.
V. WHY IS IT USEFUL TO KNOW THAT A DRUG IS ELIMINATED BY
BILIARY EXCRETION?
Considerations:
1. Drugs eliminated by biliary excretion are safer in patients with renal impairment
than drugs eliminated by renal excretion.
EXAMPLE: For inducing muscle relaxation in a patient with renal dysfunction, vecuronium or
rocuronium (which are excreted into bile) should be selected rather than pancuronium or atracurium
(which are largely eliminated by urinary excretion).
2. Drugs eliminated by biliary excretion are less safe in patients with cholestasis or
other types of significant hepatic dysfunction than drugs eliminated by renal excretion.
3. Antibiotics excreted in bile in an active form (e.g. cefoperazone, ceftriaxone,
doxycycline, rifampin) may be more effective in biliary infections (e.g. cholecystitis)
than antibiotics that are excreted into urine.
This is, however, not a firm rule. Others maintain that not the biliary but the tissue concentration of
the antibiotic is important in such infections.
4. Drugs excreted in bile may have specific adverse effects in the biliary tract.
EXAMPLE: Ceftriaxone (a dicarboxylic acid) is highly concentrated in the bile and can form its Ca2+
salt, the water solubility of which is low and thus this salt may precipitate out (see FIGURE below).
The fine precipitate (“sand”) may block the bile flow in the smaller bile ducts, causing obstructive
jaundice, which is a risk of prolonged high-dose ceftriaxone treatment. Therapy with ursodeoxycholic
acid, which dilutes the bile by inducing osmotic choleresis (i.e. enhancing bile flow by osmotic effect)
and thus promotes the gradual dissolution of the precipitate, is recommended in such condition.
N
H2N
C
S
N
C
O
O
O
O
H3 C C C
CH3 O
S
H
N
_
N
N
_
O
CH2
C
N
H2N
O
+
BILE
Ca2+
C
C
H
N
N
O
O
S
+
S
O
O
H3 C C C
CH3 O
Ca
N
N
O
CH2
C
O
Ceftriaxone
Ceftriaxone-Ca2+ salt
a cephalosporin antibiotic
poorly water-soluble, may precipitate out
III. GASTROINTESTINAL EXCRETION
D. OTHER EXCRETORY ROUTES
1. Excretion into stomach – a route for lipid-soluble weak organic bases
I. PULMONARY EXCRETION (EXHALATION)
Exhalation is an excretory route for volatile compounds, i.e. gases (N2O, toxic gases)
and volatile liquids (inhalation anesthetics, organic solvents).
MECHANISM: diffusion, driven by the blood-alveolar partial pressure gradient. Exhalation is delayed
by high solubility of the compound in blood or tissues. For example:
- N2O, desflurane, sevoflurane: relatively little soluble in blood-lipids  relatively rapidly exhaled 
rapid recovery from anesthesia. In fact, N2O so rapidly diffuses into the alveolar space that it may
dilute the O2 there, causing so called diffusional hypoxia (easily prevented by O2 inhalation).
- Halothane: highly soluble in blood  slowly exhaled  slow recovery from anesthesia.
1. Excretion by the mammary gland (via the milk) – two types of compounds:
a. Weak organic bases, by diffusion and pH-entrapment
The pH of the milk is 7.0, i.e. it is more acidic than plasma. Thus, sufficiently lipohilic basic drugs
may diffuse into the milk and, after being protonated, they are entrapped there.
Remember: such pH entrapment (albeit more efficient) may occur in the stomach (pH = 2; see
above) and in the acidic interior of the lysosomes (pH = 5, see Distribution of drugs). Drugs may
be transferred via the milk from the lactating mother into the suckling baby.
EXAMPLES:
Amphetamine, morphine, heroin, verapamil, clonidine, moxonidine – all are tertiary amines
O
Heroin
diacetylmorphine
O
H3C
Amphetamine
O
H
H3 CO
H
H3 CO
CH2 CH N
N H
Amphetamine
O
H
CH2 CH N
CH3
H
Phencyclidine
(PCP)
C CH2 CH3
Methadone
N
CH3
C
CH2 CH N
CH3
II. GLANDULAR EXCRETION
H3C C O
EXAMPLES: amphetamine, phencyclidine (PCP), methadone – all are tertiary amines.
MECHANISM: diffusion from the blood into the stomach (HCl)  protonation into positively charged
cation, which cannot diffuse back into blood = “pH-entrapment” of the drug in the gastric acid. By this
mechanism, amphetamine and PCP may accumulate in the gastric juice at concentrations exceeding
their plasma concentrations 50-100 fold.
CH3
CH3
CH3
N
CN
Verapamil
OCH3
OCH3
H3C C O
b. Extremely lipophilic compounds (not drugs), by diffusion and entrapment in milk fat
EXAMPLES: TCDD (dioxin; see its formula on the next page) and polychlorinated biphenyls
(PCBs), which are environmental contaminants. 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: humans may be exposed via the contaminated cow milk.
2. Excretion by the salivary glands
 Mechanism: diffusion
 Role in drug elimination: none
 Role in drug effect: Drugs excreted into saliva may cause local effects, such as colored sputum
(rifampin), dysgeusia (e.g. captopril), gingiva hyperplasia (phenytoin).
 Analytical significance: The salivary concentration of several drugs (e.g. primidone, phenytoin,
ethoxusimide, and carbamazepine) is similar to their protein-UNBOUND concentration in the
plasma. Measuring the salivary concentration has been used to indirectly monitor the changes in
their levels in the body – see Appendix 1. Drug abuse may be proved by detection of drugs (e.g.
cocain) in the saliva.
3. Excretion by the sweat glands
 Mechanism: diffusion
 Role in drug elimination: none
 Analytical significance: Using sweat collected in patches, illicit drugs may be detected.
CH3
NOTE: Drugs entrapped in gastric acid can move into the intestinal tract and be reabsorbed from
there, unless that is prevented by aspiration of the gastric juice. Continuous aspiration of the gastric
juice is used in amphetamine and PCP intoxications to increase the elimination of these drugs.
2. Excretion into the intestinal lumen
a. By diffusion, promoted by a non-absorbable binding substance in the intestinal lumen
 CHARCOAL as the non-absorbable binding substance. Sufficiently lipophilic drugs, e.g.
phenobarbital, carbamazepine, and theophylline, can
BLOOD
GUT
diffuse from blood across the layer of intestinal epithelial
cells into the gut. An adsorbent, e.g. charcoal, in the gut
CHARCOAL
lumen can bind such a drug, thus maintaining the
Bound
DD
DD
DD
(5)
concentration gradient for the drug and promoting its
diffusion from the capillaries into the gut lumen (see
FIGURE; DD = diffusible drug). Indeed, charcoal is given
per os for days to patients intoxicated with the abovementioned drugs to enhance their elimination from the body. In volunteers receiving i.v. injection of
phenobarbital, the elimination half-life (T1/2) of phenobarbital decreased from 110 hrs in control
subjects to 45 hrs in subjects given charcoal repeatedly for 3 days, indicating that oral administration
of charcoal accelerated the elimination of phenobarbital more than two fold.
 OLESTRA as the non-absorbable binding substance. The diffusion of extremely lipophilic
xenobiotics (which are not drugs) into gut can be facilitated by
introduction of an apolar non-absorbable substance into the
intestinal lumen in which they are dissolved and thus retained
(like in the process of solvent extraction). An example for an
apolar non-absorbable substance is olestra, a non-absorbable
fat-substitute used in potato chips. Olestra is a sucrose whose 8
-OH groups are esterified with fatty acids (see FIGURE; the
polyp-like “arms” are the long-chain fatty acids linked to sucrose
O
Cl
Cl
in the center). Olestra has been used to facilitate the intestinal
and fecal excretion of TCDD in humans. TCDD, also called
dioxin (see FIGURE), is a highly lipid-soluble environmental
Cl
Cl
O
contaminant, which resists to biotransformation and is eliminated
2,3,7,8-tetrachloro-dibenzo-p-dioxin by the intestinal-fecal route, a very slow process. The T1/2 of
(TCDD, dioxin)
TCDD is 7 years! After oral treatment of TCDD-intoxicated
patients with olestra for months, the T1/2 of TCDD decreased to 1.5 years. (Instead of olestra, liquid
paraffin may also suffice, though its long-term use may be more problematic.)
NOTE: TCDD is the most potent CYP1A inducer known. It activates the aryl hydrocarbon (Ah)
receptor, which mediates not only its CYP-inducing effect but also its various toxic effects.
Excretion into the intestinal lumen (continued)
b. By carrier-mediated transport via exporters in the luminal membrane of enterocytes
a. By MDR1 = Pgp (Substrates: digoxin, vinca alkaloids, doxorubicin, ivermectin, etc.)
Export into the intestinal lumen by Pgp causes low bioavailability of the Pgp-substrate drugs
when given orally, and may contribute to their elimination when given parenterally.
b. By MRP2 (e.g. ezetimibe glucuronide, an active metabolite, when formed in the enterocytes)
c. By the K+ secretion mechanism in the colon, which is used by Tl+, as Tl+ mimics K+.
Thallium sulfate (Tl2SO4) is a rodenticide (rat poison). In Tl-intoxication, Tl+ secreted into the
colonic lumen can be trapped by oral Berliner blue, which thus prevents the reabsorption of Tl+
from the colon and promotes Tl+ excretion into the feces. To the Tl+-poisoned patient, a Berliner
blue solution is instilled through a gastroduodenal tube, lest the patient should be blue all over.
Berliner blue = KFe[Fe(CN) 6] = potassium-ferri-hexacyanoferrate is non-absorbable from the GI
tract. It complexes K+, Tl+, and Cs + ions. K+ in the complex can be exchanged for Tl+:
Tl+
+
KFe[Fe(CN)6]
E. APPENDIX
1. Antipyrine elimination as measured by decline in the salivary concentration of antipyrine
has been used to test whether or not a drug (e.g. oxcarbazepine) induces CYP in humans. (Larkin et
al., Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects. Br. J. Clin.
Pharmacol. 31: 65-71, 1991). Antipyrine is barely bound to plasma albumin (<10%) and thus diffuses
into the saliva readily. Antipyrine is eliminated by multiple forms of CYP which catalyze its aromatic
hydroxylation (at C marked with an arrow), aliphatic hydroxylation (on the methyl group marked with
an arrow), and N-demethylation (see below):
CYP
CH3
(Phenazone)
N
CH3
*
H
O
N
O
O
Non-ionized form H5C2
of phenobarbital
lipid-soluble and diffusible
across the lipid membrane Phe
O
N
C H
O
N
N-demethylantipyrine
CH3
H
NOTES:
1. Antipyrine (or phenazone), a pyrazolone derivative NSAID, was used as a test compound by the
authors of the article cited above. They found that in oxcarbazepine-treated patients the salivary
concentration of antipyrine declined in a similar rate than in untreated subjects, therefore
oxcarbazepine (unlike carbamazepine) is NOT a CYP-inducer. (A CYP inducer would accelerate the
elimination of antipyrine.)
2. A pyrazolone derivative often used therapeutically as an antipyretic and analgesic drug is
aminophenazone (= dimethylamino antipyrine). In aminophenazone, a -N(CH3)2 group is linked to
antipyrine at the C atom marked with an asterisk. A water-soluble injectable derivative of
aminophenazone is metamizole sodium (or noraminophenazone sodium mesylate, or Algopyrin®).
H
N
H
+
O
H5C2
H
N
O
O
O
N
H
H
+
Phe
N
_
Anionic form
of phenobarbital
not lipid-soluble and not diffusible
across the lipid membrane
O
Let us calculate now the percentage of the non-ionized PB molecules at various pH values by means
of a rearranged form of the Henderson-Hasselbalch equation:
_
pK pH = lg
The percentages of the non-ionized form of PB at pH 7.2 (i.e.
at its pK), at 1, 2 and 3 pH units lower, and at 1 and 2 pH
units higher are calculated and tabulated below.
Non-ionized form
Ionized form
Non-ionized form
Percent
non-ionized
pK  pH =
lg
7.2  4.2 = 3
103
=
1000
=
1000
1
99.9%
7.2  5.2 = 2
102
=
100
=
100
1
99%
TlFe[Fe(CN)6] + K+

NOTE: A non-soluble form of Berliner blue, i.e. Fe4[Fe(CN)6]3 = ferri-hexacyanoferrate, is available
in tablets (Radiogardase®) at counter-terrorism agencies. It may be used for decontamination of
individuals exposed orally to 137Cs or 210Tl. These radioactive nuclides may be present in “dirty
bombs”. 137Cs is -emitter (T1/2 = 30 yrs), 210Tl -emitter (T1/2 = 73 days). These are bound by
ferri-hexacyanoferrate, thus this complexing agent prevents their absorption from the gut.
Antipyrine
2. Why can we increase the urinary excretion of phenobarbital by alkalinization of the renal
tubular fluid? Illustration in a tabulated form. Phenobarbital (PB) is a weak acid with a pK of 7.2.
It can exists in non-ionized form (left) and, after being deprotonated, in anionic form (right). It is the
pH of the solution in which PB is dissolved that determines the proportion of these forms.
Ionized form
Remember: pK is the pH at
which half of the molecules are
in non-ionized form and half
are ionized. Accordingly, 50%
of PB molecules (whose pK is
7.2) are non-ionized at pH 7.2
(see the shaded row).
The table demonstrates that by
lowering the pH in 1 unit steps
from 7.2 the percentage of the
1
50%
7.2  7.2 = 0
100
=
1
=
non-ionized
PB
molecules
1
gradually increases, i.e. they
1
convert into more lipid-soluble,
10%
7.2  8.2 = -1 10-1
=
0.1
=
10
more
membrane-diffusible
form. In contrast, by increasing
1
1%
7.2  9.2 = -2 10-2
= 0.01 =
the pH in 1 unit steps from 7.2
100
the percentage of the nonionized PB molecules gradually decreases, i.e. they convert into anionic, less lipid-soluble, less
membrane-diffusible form. As discussed above, this explains why we can decrease the reabsorption
of PB from the renal tubules by alkalinizing the tubular fluid by means of NaHCO3 infusion. Note that
by increasing the pH of the urine from 6.2 (a typical value) to 8.2 by bicarbonate the non-ionized form
of PB that can be reabsorbed by diffusion from the renal tubules decreases from 90% to 10%.
7.2  6.2 = 1
101
=
10
=
10
1
90%
This procedure is used to enhance the urinary excretion of PB in the PB-intoxicated patient.
Acidification would have an opposite effect: the renal reabsorption of PB would increase and its
urinary excretion would decrease. Moreover, more PB would diffuse into the brain, which could
worsen the condition of the PB-intoxicated patient. Therefore, the urine alkalinization with a carbonic
anhydrase inhibitor is contraindicated because such drugs not only alkalinize the urine but also cause
systemic acidosis, thus promoting the diffusion of weak acids, like PB, from blood into brain.
It is well known that NaHCO3 infusion increases the urinary excretion of salicylate (the toxic
metabolite of aspirin) and therefore NaHCO3 is given to the aspirin-intoxicated patient. However,
how urinary alkalinization increases salicylate excretion is uncertain. Some claim that the effect of
NaHCO3 cannot be due to increased ionization of salicylic acid (pK 3) as that is practically complete
in the physiologic urinary pH range. Indeed, at pH 5, 6, 7 and 8 as much as 99, 99.1, 99.99 and
99.999% of salicylic acid, respectively, must be anionic (charged) and not reabsorbable. One may
reason, however, that at these pH values 1, 0.1, 0.01, and 0.001% of salicylic acid must be nonionized and reabsorbable. Thus, alkalinization markedly decreases the proportion of reabsorbable
form of the drug. If reabsorption of the non-ionized salicylic acid is very rapid (consider that the
ionized/non-ionized forms are in equilibrium), decreasing the proportion of the non-ionized molecules
from 1% to 0.001% can still reduce the reabsorption and increase the excretion of salicylic acid.
3. Why does water-solubility promote and lipid-solubility retard the excretion of
compounds? What is biomagnification? Why did the falcons of Long Island die?
While lipid-solubility facilitates and water-solubility hinders absorption of drugs by diffusion (see Part
3), excretion is affected by the solubility in just the opposite way: water-solubility favors the excretion
of drugs and metabolites, whereas lipid-solubility hinders the excretion of compounds.
Water-solubility favors the excretion of nonvolatile compounds for the following reasons:
 In the renal glomeruli, only compounds dissolved in plasma water can be filtered;
 Transporters in hepatocytes and renal proximal tubular cells are specialized for secretion of highly
hydrophilic organic acids and bases;
 Only hydrophilic chemicals are freely soluble in the aqueous urine and bile; and
 Lipid-soluble compounds are readily reabsorbed from the renal tubules and/or the biliary and GI
tract by transcellular diffusion.
Lipid-solubility may favor accumulation of compounds (a) in the body, and (b) in the living
environment along the food chain, a process called biomagnification. Here is the explanation:
 There are no efficient excretion mechanisms for nonvolatile, highly lipophilic compounds, which
are typically non-drug chemicals, such as chlorinated hydrocarbon insecticides, like DDT.
 If such chemicals are resistant to biotransformation (one of the mechanisms of elimination), they
are eliminated very slowly and tend to accumulate in the body upon repeated exposure.
 If such chemicals are also resistant to degradation in the environment, they may accumulate along
the food chain, reaching the highest concentration in the organism at the top of the food chain.
Why did the falcons die? The story of biomagnification of DDT. Around 1960, American
environmentalists observed that the population of peregrine falcons markedly decreased in Long
Island, NY. Therefore, the US Environmental Protection Agency (EPA) carried out an investigation
and found DDT in the environment. In that era DDT was widely used as an insecticide, for example
against potato beetle. EPA verified that the concentration of DDT in the food chain of falcons rose
progressively and reached the highest levels in these birds of prey (see table). The highly lipophilic
DDT (see formula) killed the birds mainly during winter when less prey was available, causing
decrease in adipose tissue mass and redistribution of DDT (which is neurotoxic) from the fat into the
brain. This story was published in a book entitled Silent spring (1962) written by Rachel Carson.
Peregrine falcon
Dichloro-diphenyl-trichloro-ethane
DDT
Cl
CH
Cl
Cl C Cl
Cl
Potato beetle
Concentration of DDT Relative co nc.
of DDT
ppm = µg/g = mg/k g
Soil
0.0005
1
Water: - Planktons
0.04
80
- Algae-eating fish
0.7
1 400
- Carnivorous fish
2
4 000
Fishing birds, falcons
50
100 000
Sample analyzed
Why did DDT undergo biomagnification? Because:
1. DTT resists environmental degradation  DDT persists in the environment (T1/2 = 2-15 years).
2. DDT is highly lipid-soluble  DDT is readily taken up by organisms and then it accumulates in
lipid-rich tissues (e.g. adipose tissue).
3. DDT resists biotransformation to water-soluble metabolites in the body  its elimination from
the body is slow.