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Part 3. ABSORPTION OF DRUGS
A. ABSORPTION FROM THE GASTROINTESTINAL TRACT
I. MECHANISMS
1. Diffusion
2. Carrier-mediated transport (by secondary and tertiary active transporters)
3. Receptor-mediated endocytosis
II. INFLUENCING FACTORS
1. Motility of the GI tract: gastric emptying, intestinal propulsive motility
2. Luminal pH
3. Luminal content – quantity
4. Luminal content – quality
acidity in the stomach; intake of fat, protein, fruit juice, vegetarian diet, Ca2+, non-absorbable resins
III. ORAL BIOAVAILABILITY (F)
1. Definition of F
2. Determination of F = AUCpo : AUCiv
3. Potential causes of incomplete oral bioavailability:
a. Incomplete release of the drug from the formulation
b. Degradation of the drug molecule in the GI lumen
c. Poor solubility of the drug in the GI juices (e.g., phenytoin, itraconazole)
d. Poor diffusibility of the drug molecule across the GI mucosa (strong acids, strong bases)
e. Presystemic elimination (PSE) of the drug = first pass elimination – intestinal PSE (by
biotransformation, and/or export back to the lumen) and hepatic PSE (by biotransformation)
B. ABSORPTION FROM THE ORAL, NASAL AND RECTAL MUCOSA
I. COMMON FEATURES
A. ABSORPTION FROM THE GI TRACT
I. MECHANISMS
1. Diffusion: probably important for most drugs, at least partly
2. Carrier-mediated transport: important for several drugs, at least partly
 Secondary active transport:
- Concentrative nucleoside transporter (CNT, Na+-coupled): ribavirin, acyclovir
- Phosphate transporter (NPT2b; Na+-coupled): foscarnet
- Sodium-dependent glucose transporter 1 (SGLT1, Na+-coupled): glucose
 Tertiary active transport:
- Monocarboxylate transporter (MCT, H+-coupled): aspirin, valproate, pravastatin
- Peptide transporter (PEPT, H+-coupled, see Fig. in Part B): -lactam antibiotics, e.g. ceftibuten;
ACE inhibitors, e.g. captopril, lisinopril; valacyclovir (the antiviral acyclovir coupled to valine)
- Divalent metal transporter (DMT, H+-coupled): Fe2+ (Cd2+)
- Organic anion-transporting polypeptide (OATP): fexofenadine, montelukast, atenolol, aliskiren
- Large neutral amino acid transporter 1 (LAT1): L-DOPA, -methyldopa, gabapentin
Intestinal lumen
Blood side
2K+
11
HOOC
O
N
HN
H2N
N
N
H
valacyclovir
C
N
O
O
O
ADP 3Na
Na
NH2
N
C
C. ABSORPTION FROM THE SKIN
S
H
+
2
H+
O
ceftibuten
H2N
ATP
COOH
N
O
II. DRUGS SUITED FOR ABSORPTION FROM THE ORAL, NASAL AND RECTAL MUCOSA
I. FEATURES
NH2
lisinopril (ACEI)
C
C
N
H
CH2
S
3
N
H+
COOH O
COOH
X-
II. INFLUENCING FACTORS
1. Chemical factors
a. Lipid solubility
b. Concentration
3. Receptor-mediated endocytosis: vitamin B12-IF complex; folates and methotrexate
2. Biological factors
a. The thickness of stratum corneum
b. Dermal circulation
II. INFLUENCING FACTORS
3. The size of the exposed area
D. ABSORPTION FROM THE LUNG
I. FEATURES
1. Chemicals suited for pulmonary absorption
2. Mechanism and factors promoting pulmonary absorption
II. OBJECTIVES FOR DRUG ADMINISTRATION BY INHALATION
1. Systemic effect
2. Local effect
E. APPENDIX: More complete oral absorption and slower elimination of penicillin in neonates
by folate receptor 1, FOLR1 (and also by transporters: RFTC1 and PCFT – see Part 2).
Consider: The proximal small intestine (SI) has a vast absorptive surface compared to
the stomach, owing to the villi on the mucosa and the microvilli of enterocytes.
1. Motility of the GI tract: gastric emptying (GE), intestinal propulsive motility (PM)
 Gastric emptying: determines how soon the drug reaches the proximal SI
- Delayed GE caused by a fatty meal, drugs (e.g. anticholinergics), or disease (e.g. migraine)
delays the onset of drug absorption.
- Fastened GE caused by fasting state, intake of large volume of water, drugs (e.g. prokinetics)
promotes the onset of drug absorption.
 Intestinal PM: determines how long the drug resides in the SI (normally for 3-4 hrs)
- Sluggish motility improves the absorption of incompletely absorbed drugs (e.g. furosemide,
ciprofloxacin, bisphosphonates, acyclovir, metformin, captopril, L-dopa, gabapentin)
- Diarrhea may compromise the absorption of drugs, thus it may cause contraceptive failure
despite taking an oral contraceptive.
2. Luminal pH
Consider: Ionization, and in turn the lipid solubility and diffusibility across the lipid
bilayer, of weak (but not strong) organic acids and bases depends on pH.
Example: Using the Henderson-Hasselbalch equation (see Part 2), the ratio of nonionized [NI] and ionized [I] molecules of acetylsalicylic acid (aspirin, a weak acid)
and amphetamine (a weak base) is calculated at the pH of the stomach, the intestine
and the plasma, knowing the pKa values of these drugs and the pH at these sites.
Acetylsalicylic acid, pKa = 3.5
COOH
COO
O C
CH 3
H
+
O C
O
Amphetamine, pKa = 9.5
_
O
CH 3
CH2 CH CH3 H+
NH2
[NI]/[I] = 10 pKa – pH
CH2 CH CH3
+
NH3
[NI]/[I] = 10 pH – pKa
Remember: the non-ionized molecules are relatively lipid soluble and diffusible across
the lipid bilayer of the membrane, whereas the ionized molecules are not.
NON-IONIZED MOLECULES / IONIZED MOLECULES
Stomach, pH = 2
Intestine, pH = 6
Plasma, pH = 7.4
Acetylsalicylic acid, pKa=3.5
32 (32:1)
0.0032 (32:10,000)
0.00012 (12:100,000)
Amphetamine, pKa=9.5
0.000000032 (32:1,000,000,000)
0.00032 (32:100,000)
0.0080 (80:10,000)
Implications of the calculated ratios:
 Absorption of weak organic acids (e.g. aspirin) may start from the stomach (because of the
favorable [NI]/[I] ratio there), but is likely to be completed in the proximal SI (because of the
large surface area there).
 Absorption of weak organic bases (e.g. amphetamine) can not start from the stomach
(because of the highly unfavorable [NI]/[I] ratio there), but they are absorbed from the proximal SI
(because of the large surface area there). Do not forget that [NI] and [I] molecules are in
equilibrium: when NI molecules are absorbed some I molecules become NI molecules to maintain
the equilibrium.
 As the table indicates, there is a concentration gradient for the non-ionized amphetamine between
the plasma and the stomach. Therefore, amphetamine diffuses from the plasma into the stomach,
where it becomes protonated, and in the cationic form it cannot diffuse back into the blood: pH
entrapment. To remove amphetamine from the stomach of the amphetamine-intoxicated patient,
the gastric juice is aspirated continuously. The street drug phencyclidine (PCP) behaves similarly.
NOTE: Ambenonium is a long-acting cholinesterase inhibitor without CNS effects for treatment of
myasthenia gravis. This disease requires prolonged therapy, therefore parenteral ambenonium is
impractical. Therefore a compromise is made: the multiple of the parenteral dose of ambenonium is
given orally (to compensate for its very poor GI absorption) to reach therapeutic concentration at the
neuromuscular junction, where it blocks the hydrolysis of acetylcholine and improves transmission.
 Absorption of some drugs (e.g.
erythromycin) is significantly
delayed by food. This necessitates
administration of erythromycin on empty
stomach (or rather, its substitution with
congeners that are better absorbed,
e.g. clarithromycin, azithromycin).
4. Luminal content – quality
Consider: Only molecules in
solution can be absorbed from the
GI tract, solid particles cannot!
There are drugs whose dissolution
requires acid (e.g. itraconazole),
whereas the dissolution of others
(e.g. phenytoin) is facilitated by lipids.
 Low acidity in the stomach. This impairs the dissolution of itraconazole, and in turn,
its absorption, whereas the absorption of itraconazole is improved by taking it with an
acidic beverage, such as Coca-Cola.
 High-fat meal. This promotes the
dissolution of hydrophobic lipidsoluble drugs, such as phenytoin,
cyclosporine, sirolimus, probucol,
griseofulvin and ticlopidine, and
in turn their absorption (see
figure). However, high fat meal
also decreases gastric emptying
and thus may slow absorption of
some drugs (e.g. zidovudine).
 High-protein meal. This results in
3. Luminal content – quantity
 Drugs are typically better absorbed from empty stomach. This is especially true
for highly ionized drugs, such as the bisquaterner (di-cationic) ambenonium (see fig.)
and the bisphosphonate ibandronate, which are barely absorbed from the gut, as
they lack lipid solubility. Yet, their absorption is improved when these drugs are taken
in the fasted state (as recommended), as compared to the non-fasted condition.
NOTE: In figures on ambenonium, phenytoin and fexofenadine (see the next two pages), the plasma
concentrations of drugs versus time are shown after oral dosing. For these drugs, the area under the
plasma concentration vs. time after per os administration (AUCpo) is proportional to their intestinal
absorption. Thus, decreased AUCpo in these figures indicates decreased intestinal absorption.
high concentration of amino acids
and dipeptides in the intestinal
lumen, which competitively inhibit
the absorption of drugs, such as
- L-DOPA by the L-type amino acid transporter 1 (LAT1), and
- Captopril by the peptide transporter (PEPT).
 High intake of fruit juices. This decreases the absorption of fexofenadine via OATP
in enterocytes because bergamottin, a furocumarin in fruits and juices like grapefruit
juice (GFJ), orange juice (OJ) and apple juice (AJ), inhibits OATP (see figure).
 Administration of non-absorbable ion-exchange resins or adsorbents:
To decrease the GI absorption of some endogenous compounds (e.g. bile acids),
inorganic ions and drugs may be a therapeutic objective.
- Non-absorbable ion-exchange resins are used to decrease the absorption of:
> Bile acids by cholestyramine, an anion-exchange resin with quaternary N atoms,
which is used in hypercholesterolemia and pseudomembranous colitis.
NOTE: As anion-exchange resins can bind not only the anionic bile acids but anionic drugs as
well, their simultaneous administration with such drugs should be avoided.
> Phosphate by sevelamer, an anion-exchange resin with -NH2 groups,
which is used in renal failure to prevent hyperphosphatemia.
> K+ by polystyrene sulfonate, a cation-exchange resin with sulfonate groups,
which is used in hyperkalemia to lower K+ absorption.
FIGURE: Plasma fexofenadine concentration-time profiles in persons (n=10) orally administered
fexofenadine (120 mg) with 300 ml water, 25% grapefruit juice (25% GFJ), grapefruit juice (GFJ),
orange juice (OJ), or apple juice (AJ) followed by 150 ml of the same fluid every 0.5 hr for 3 hrs.
CHOLESTYRAMINE
(an anion-exchange resin)
decreases hypercholesterolemia
by binding bile acids in the intestine
CH3
CH2 CH
CH2 N
+
H3C
Cholic Acid
OH
O
CH3
CH3
decreases the absorption of Fe2+ because these anions form insoluble salts with Fe2+.
CH2 CH
CH2 S
_
O
O
n
COO
n
_
K
+
CH3
CH3
 High intake of Ca2+ (milk, yoghurt):
Absorption of tetracyclines, fluoroquinolones (see figure) and
mycophenolate mofetil is decreased by
Ca2+ because these drugs form nonabsorbable chelates with Ca2+ in
dairy products. The intake of Ca2+, Mg2+,
Al3+, Fe2+, Bi3+ found in drugs (e.g.
antacids and supplements) causes
similar effects.
Dietary or therapeutic calcium also
impairs the absorption of strontium
ranelate (used for osteoporosis)
because Ca 2+ at high concentration
displaces Sr2+ from its complex with ranelic acid, thus reducing its absorption.
CH CH2 CH CH2
CH CH2 CH CH2
NOTES: (1) The AUCpo of some other drugs absorbed from the gut through OATP (e.g. atenolol and
aliskiren) is also decreased by fruit juices. (2) As opposed to fexofenadine, the plasma concentrations
of several drugs (e.g. buspirone and simvastatin) were markedly increased when taken with GFJ
(their AUCpo was increased several fold – see Part 6 for more detail). This is attributed to the fact
that these drugs are eliminated by CYP3A4-catalyzed biotransformation and that bergamottin and
naringenin (constituents of the GFJ) are not only OATP inhibitors but also inhibitors of CYP3A4, the
major form of CYP in the GI mucosa and the liver (see Part 6 for more detail). In contrast,
fexofenadine is not biotransformed in the body but is excreted into bile largely unchanged.
 High intake of phytate, tannate, oxalate, or phosphate (vegetarian diet):
POLYSTYRENE SULFONATE
(a cation-exchange resin)
decreases hyperkalemia
by binding K+ in the intestine
HO
OH
- Adsorbents (e.g. charcoal) are used to decrease the absorption of drugs after
oral overdose.
NOTE: Adsorbents (e.g. charcoal) may also be used to increase the elimination of some
drugs that are sufficiently lipophilic to diffuse from the blood across the layer of intestinal
epithelial cells into the gut, such as phenobarbital, carbamazepine, theophylline. Charcoal in the
gut lumen can bind such a drug, thus maintaining the concentration gradient for the drug and
promoting its diffusion from the capillaries into the intestine. Indeed, charcoal is given per os for
days to patients intoxicated with the above-mentioned drugs in order to enhance their
elimination from the body. Experimental evidence indicates that charcoal can indeed enhance
the elimination of phenobarbital. In volunteers receiving i.v. phenobarbital, the elimination halflife of phenobarbital decreased from 110 hrs in control subjects to 45 hrs in subjects given
charcoal repeatedly for 3 days.
III. ORAL BIOAVAILABILITY (F)
The major sites of presystemic elimination (with examples):
1. Definition: Oral bioavailability is the fraction (F) of the orally administered dose
 The intestinal mucosa; intestinal presystemic elimination may occur by:
that reaches the SYSTEMIC circulation.
2. Determination of F: To determine F, in an ideal case, human subjects are given
the drug in the same dose once i.v. and – and after the drug had been eliminated –
once p. os. After dosing, the concentration of the drug in the plasma is repeatedly
measured and plotted against time. F is calculated as shown from the areas under the
plasma conc. vs. time curves (AUC). The highest value of F is 1. This indicates that the
oral bioavailability of the drug is complete, i.e. 100% of the oral dose reaches the
systemic circulation. If F is < 1, the oral bioavailability of the drug is incomplete.
- Biotransformation catalyzed by:
> CYP3A4 (the most abundant CYP in human enterocytes): cyclosporine (F = 0.3),
midazolam (F = 0.4), fluticasone (F < 0.01), ergotamine (F < 0.01)
> MAO-A: tyramine (For this reason, irreversible MAO-A inhibitors cause the cheese reaction.)
sumatriptan (F = 0.2), zolmitriptan (F = 0.4), rizatriptan (F = 0.4)
> SULT: terbutaline (F = 0.1), isoprenaline
> UGT:
morphine (F = 0.2), labetalol (F = 0.2)
- Export from the enterocytes back into the gut via transporters, typically
Pgp/MDR1 (or MRP2 and/or BCRP). Drugs exported by Pgp and their F values:
F = AUCp.o. : AUCi.v.
vinca alkaloids
loperamide
doxorubicin
dabigatran
0.02
0.03
0.05
0.07
paclitaxel
verapamil
cyclosporine
digoxin
0.07
0.2
0.3
0.6
 The liver (hepatic presystemic elimination) by uptake + biotransformation:
3. Potential causes of incomplete oral bioavailability:
a. Incomplete release of the drug from the tablet or capsule, as the tablet or
capsule incompletely disintegrates – a problem caused by poor drug formulation.
b. Degradation of the drug in the lumen (by digestive enzymes or acid)
- by hydrolysis – e.g. peptides (insulin) by peptidases, esters (Ach, procaine) by esterases,
amides (penicillin by gastric acid – see Appendix): lack of acid in the neonatal
stomach results in high oral bioavailability of penicillin in newborn babies.
- by oxidation – e.g. catecholamines (are spontaneously oxidized to quinones)
c. Poor solubility of the drug in the intestinal fluids. Poor dissolution can limit the
absorption of some drugs (e.g. phenytoin and itraconazole), as mentioned above.
d. Poor diffusibility of the drug across the mucosa (highly ionized drugs)
- Strong acids: bisphosphonates, cromoglycate, suramin, deferoxamine, EDTA
- Strong bases: aminoglycosides (cont. protonated NH2 groups), tubocurarine (quat. N)
NOTE: Because these drugs are very poorly absorbed from the GI tract, their oral dose must be
increased several fold over their i.v. dose in order to reach therapeutic blood levels after per os
administration. For example:
- Neostigmine (cholinesterase inhibitor):
i.v.: 0.5 mg, per os: 30 mg
- Pyridostigmine (cholinesterase inhibitor): i.v.: 1 mg, per os: 60 mg
- Ibandronate (bisphosphonate, for osteoporosis): i.v.:
3 mg once in every 3 months
per os: 150 mg once a month
e. Presystemic elimination of the drug (= first pass elimination)
Consider: Before reaching the systemic circulation, an orally administered drug passes through the
intestinal mucosal epithelial cell layer (to reach the portal blood), then the liver (to reach the inferior v.
cava), and finally the lung. At each of these sites drug molecules may be eliminated even before
reaching the systemic circulation which carries most drugs to the site of their pharmacologic action.
Most typically, such presystemic elimination takes place in the enterocytes and the liver.
-
verapamil:
lidocaine:
propranolol:
nitroglycerin:
by CYP, via N-demethylation (F = 0.2; i.v. dose 5 mg, p.o. 40-80 mg)
by CYP, via N-deethylation (F = 0.3)
by CYP, via aromatic hydroxylation and N-dealkylation (F = 0.3)
by organic nitrate reductase, aldehyde dehydrogenase (?) (F < 0.01)
 Both the intestinal mucosa and the liver, e.g.:
- morphine:
by glucuronidation in both the enterocytes and liver (F = 0.2)
- buspirone:
by CYP3A4-catalyzed N-dealkyl. in enterocytes and liver (F = 0.05)
- cyclosporine: by Pgp-mediated export from the enterocytes and
CYP3A4-catalyzed hydroxylation in enterocytes and liver (F = 0.3)
- ergotamine: by Pgp-mediated export from the enterocytes and
CYP3A4-catalyzed oxidation in enterocytes and liver (F < 0.01)
4. Consequences of low oral bioavailability:
 Low F is unfavorable for drugs that reach their site of action by the systemic
circulation (i.e. for most drugs).
Some of these drugs (e.g. vinblastine, doxorubicin, paclitaxel) must be used only parenterally.
Others can still be given orally (e.g. nitroglycerin, verapamil, dabigatran), however, at a dose much
higher than the dose that would be effective if the F value were close to 1.
 Low F may be favorable for drugs whose target site is presystemic. Examples:
- High presystemic elimination by hepatic uptake via OATP1B1 is favorable
for HMG-CoA reductase inhibitors (e.g. simvastatin, pravastatin) for two reasons:
(1) it directs statins into the liver, their major site of therapeutic action, and
(2) it diverts statins from the skeletal muscles, the site of their myotoxic action.
- Poor GI absorption and export by Pgp from the enterocytes back to the gut
may contribute to maintenance of high intestinal (and low systemic) drug concentration. This may
be beneficial for drugs that act on/in the GI tract (e.g. the GI spasmolytic pinaverium bromide
and methylhomatropine, the anti-inflammatory mesalazine, the obstipant loperamide, the
anthelminthic ivermectin, and the antibiotic vancomycin  for pseudomembranous colitis).
Pgp (MDR1) works as an exporter at multiple sites:
e.g. vincristine and vinblastine
(can be given only parenterally)
B. ABSORPTION FROM
THE ORAL, NASAL AND RECTAL MUCOSA
I. COMMON FEATURES
1. Mechanism: diffusion
2. Small absorptive surface area
3. Drugs are not exposed to HCl and high concentration of digestive enzymes
4. Drugs avoid the intestinal mucosa and the liver, thus are not subjected to
intestinal and hepatic presystemic elimination.
II. FORMULATIONS AND DRUGS suited for absorption from the:
ORAL CAVITY
e.g. digoxin
(excreted by renal tubular secretion)
(can be given only parenterally
 Formulation: sublingual (buccal) tablet, spray
 Drugs given sublingually for systemic effect: relatively lipophilic compounds
e.g.: - Nitroglycerine – for angina
- Fentanyl – for pain in cancer patients
- Prochlorperazine – to relieve nausea in migraine
NASAL CAVITY
 Formulation: nasal spray
 Drugs given nasally for systemic effect:
a. Oligopeptides (diffuse across the mucosa by the paracellular route):
e.g.: - Desmopressin – an ADH analogue, for diabetes insipidus
- Oxytocin – to promote lactation (milk ejection)
- Calcitonin – in osteoporosis and hypercalcemia
- Buserelin – an LH-RH analogue, for prostatic cancer
e.g. loperamide (IMODIUM)
(an opioid which cannot enter the brain but
can act on the gut as an antidiarrheal drug)
b. Non-peptide drugs:
e.g.: - Butorphanol – an opioid; for analgesic effect
- Sumatriptan – an 5HT1D receptor agonist, used in migraine attack
- Estradiol – in menopause, osteoporosis
- Cyanocobalamin – given when vitamin B12 is not absorbed from the gut
RECTUM
 Formulations: rectal suppository, enema
 Drugs given rectally for systemic effect when:
- oral administration is difficult (babies, vomiting),
- exposure of the gastric mucosa or the liver to high concentrations of the drug is
undesirable (gastric ulcer, liver disease),
- oral dosing results in very high presystemic (first pass) elimination of the drug,
e.g. ergotamine (see the figure on the next page).
FIGURE: Ergotamine (used to relieve migraine) reaches 10 times
higher blood levels after rectal administration than after oral dosing.
C. ABSORPTION FROM THE SKIN
ERGOTAMINE IN PLASMA (pg/ml)
I. FEATURES
100
1. Operative for drugs that are applied to the skin in:
a. Dusting powders, solutions, ointments – for topical effects
b. Transdermal patches – for systemic effects
2. Mechanism: diffusion; the main barrier is stratum corneum
2 mg ergotamine rectally
after cleansing enema
II. INFLUENCING FACTORS
1. CHEMICAL FACTORS
a. Lipid solubility
 Unlike hydrophilic anesthetics, e.g. procaine, lipid soluble local anesthetics, e.g.
tetracaine, are useful for surface anesthesia because they more readily diffuse
through the epidermis to reach the sensory nerve endings in the dermis.
10
1
2 mg ergotamine orally
to fasted patients
From: Sanders et al.
Eur. J. Clin. Pharm. 30: 331, 1986.
0.1
0
2
4
6
8
10
12
14
16
18
20
22
O
Procaine
H2N
C O CH2 CH2
C2H5
N
24
TIME AFTER ERGOTAMINE ADMINISTRATION (hrs)
C2H5
H
CH3 CH2 CH2 CH2 N
NOTE: Poor oral bioavailability of ergotamine is thought to be due to its
intestinal and hepatic presystemic elimination. This appears to originate from its
(1) intestinal and hepatic biotransformation by CYP3A4 (the predominant form of CYP
in both hepato- and enterocytes) and (2) export by P-glycoprotein (Pgp) from the
enterocytes into the gut.
Several drugs that are inhibitors of CYP3A4 or Pgp or both, such as erythromycin,
verapamil and ritonavir (a HIV protease inhibitor), may cause ergotism in patients
treated with these drugs and who also receive ergotamine. Ergotism is characterized
by signs of peripheral ischemia (headache, intermittent claudication, muscle pain,
numbness, coldness and pallor of the extremities; gangrene may occur).
Ergotamine is a vasoconstrictor due to its 5HT1 and α1-adrenoceptor agonistic actions
and it has a beneficial effect in migraine attack.
O
C O CH2 CH2
CH3
N
CH3
Tetracaine is lipophilic due to the 4 C-atom-long aliphatic chain
linked to the p-amino group.
 Drugs that are both lipid soluble and potent enough can be administered in topical
patches for systemic effects. Examples: nitroglycerin, scopolamine, nicotine, fentanyl,
lidocaine, estradiol, testosterone, rotigotine.
 To make some acidic NSAIDs suitable for use in subdermal inflammations (e.g.
tendinitis) in topical preparations, the –COOH group in such drug is esterified with an
alcohol in order to make the drug more lipophilic and diffusible through the skin.
Examples: - salicylic acid + methanol  methylsalicylate
- flufenamic acid + ethylene glycol  etofenamate (may be used in a topical gel)
 Lipid soluble chemicals may cause intoxication upon dermal exposure.
Examples: OP insecticides, hexane (a solvent), pentachlorophenol (a fungicide).
b. Concentration (as the driving force for dermal absorption)
A tragic example: Severe and fatal intoxications with encephalopathy resulted in the past in France
when a 6%-hexachlorophene powder was accidentally manufactured and used on babies as
dusting powder. (The antiseptic concentration of hexachlorophene is 0.5-1%; hexachlorophene is
no longer used due to its unavoidable contamination with dioxin, also called TCDD.)
2. BIOLOGIC FACTORS
a. The thickness of stratum corneum (as the main diffusion barrier) determines
the degree of dermal absorption of drugs and other chemicals – see table:
AREA
RELATIVE ABSORPTION OF
C14-CORTISOL
sole
palm
arm
back
scalp
armpit
forehead
submandibular area
scrotum
1
6
7
12
25
26
43
93
300
Examples demonstrating the significance of the thickness of str. corneum:
 Scrotum cancer was prevalent in chimney sweeps, as described by Sir Percival Pott
in 1775. The causative chemicals are polycyclic aromatic hydrocarbons, which diffuse into the
keratocytes readily in the skin of the scrotum where, the str. corneum is lacking (table above).
 In infants (whose skin does not contain str. corneum) intoxications with chemicals
have been caused through dermal exposure. Historical examples:
- Pentachlorophenol (PCP): lethal intoxications by PCP-contaminated diapers
St. Louis, MO, 1967: As a fungicide, PCP was added to the rinsing water of the diapers.
- Warfarin: lethal intoxications by warfarin in baby dusting powder
Saigon, 1981: 177 babies died of hemorrhages caused by a baby dusting powder which
contained warfarin by mistake.
b. Dermal circulation – increased by heating and rubbing
Examples demonstrating the significance of dermal circulation:
 Taking sauna increases drug absorption from a topical patch.
D. ABSORPTION FROM THE LUNG
I. FEATURES
1. Chemicals suited for pulmonary absorption – inhalable substances:
a. Gases (therapeutic: e.g. N2O, CO2; toxic: e.g. CO, HCN, H2S)
b. Vapors of liquids (therapeutic: e.g. amyl nitrite, desflurane;
toxic: e.g. organic solvents, metallic Hg)
c. Vaporized solutions (e.g. terbutaline solution – although absorption is undesirable)
d. Small particle-size powder (e.g. insulin)
2. Mechanism: diffusion, which is influenced by:
a. Chemical factors:
 Inhaled concentration: Among others, the inhaled concentration determines the
onset of anesthetic effect of an inhalation anesthetic (i.e. the speed of induction).
 Lipid solubility: The degree of lipid solubility determines (in part by influencing
pulmonary absorption) the potency of inhalation anesthetics.
b. Biological factors – the pulmonary absorption of compounds is promoted by:
 The huge absorptive surface area (the alveolar surface is ~100 m2)
 The small diffusion distance across the type-I pneumocytes (~0.5 m)
 The large pulmonary blood flow (= cardiac output)
These extremely favorable biological factors permit sufficient transport even for large
peptides, such as insulin (6 kDa), from the alveolar space into the pulmonary blood.
Indeed, in 2014 US FDA approved Afrezza (rapid-acting insulin inhalation powder with particle size
of 1 μm or less) for treatment of diabetes.
II. OBJECTIVES of drug administration by inhalation
 In hot weather pesticide sprayers are more likely intoxicated than in mild weather.
1. SYSTEMIC EFFECT – alveolar absorption is desirable
 Rubbing, when decontaminating the skin, may increase the dermal absorption of a
contaminant. So, do not rub the skin when decontaminating the skin of a sprayer!
Examples: - Inhalation anesthetics (gases, e.g. N2O; vapors, e.g. sevoflurane)
- Amyl nitrite for angina
 Inflammation: in addition to the higher dermal circulation other factors may also
contribute to increased dermal absorption of drugs in dermatitis.
2. LOCAL EFFECT on the bronchial mucosa or smooth muscle
In this case alveolar absorption of the drug is undesirable!
3. THE SIZE OF THE EXPOSED AREA
Examples demonstrating the significance of the exposed area:
 Infants are susceptible for intoxications by dermal exposure (see above)
not only because of the lack of str. corneum, but also because they have large body
surface relative to their body weight.
 The size of topical patch (e.g. 20-30-40 cm2) determines the dose rate
of a drug administered in a transdermal patch. By increasing or decreasing the size
of the patch, one can increase or decrease the dose rate proportionately.
Examples for inhaled solutions as antiasthmatics:
 Bronchodilator spray (e.g. terbutaline, fenoterol in combination with ipratropium)
 Glucocorticoid spray (e.g. beclomethasone, budenoside, fluticasone)
The fluid droplet or particle size determines the site of deposition:
>10 μm: deposition in the upper airways
1-5 μm: deposition in the bronchioles – desirable for asthmatic patients.
<1 μm: passage to the alveolar space, from where the drug is readily absorbed and
then causes systemic effect – undesirable for asthmatic patients.
E. APPENDIX
Penicillin is more completely absorbed and more slowly eliminated in neonates
than in children
On oral administration of penicillin G (benzylpenicillin; 22,000 units/kg) the AUC0-6hr was found to be
7-fold larger in neonates than in children (Huang and High, J. Pediatr. 42: 658-668, 1953; see the left
figure). This is attributed to two pharmacokinetic alterations in the neonatal age.
1. In the newborn, the oral bioavailability of penicillin G is much higher than in children or adults.
This is due to lacking hydrochloric acid secretion in the neonatal stomach. Benzylpenicillin is acidlabile, i.e. the amide bond in the four-membered -lactam ring undergoes hydrolysis in the gastric
acid. In the absence of HCl from the newborn stomach, penicillin is not degraded, therefore it is orally
bioavailable. When gastric acid secretion starts (a few days after birth) penicillin becomes degraded
in the stomach, resulting in its low oral bioavailability.
2. In the newborn, the elimination of penicillin G is much slower than in children or adults.
Benzylpenicillin is eliminated by renal excretion, i.e. glomerular filtration and tubular secretion. As an
organic acid, penicillin is taken up into proximal convoluted tubular cells by OAT1 (a tertiary active
transporter; see under Transport mechanisms), and exported across the luminal membrane (by the
primary active MRP4 and/or the exchanger OAT4) into the tubular fluid. In the newborn, the renal
excretory function is immature: both the GFR and the capacity of tubular secretion is low (the latter is
due to diminished expression of transporters). The figure on the right indicates, that elimination of
penicillin G (22,000 units/kg) after intramuscular injection is slower in neonates as compared to
children, resulting in approximately 4-fold longer elimination half-life of penicillin in the babies than in
children above 2 years of age (Huang and High, J. Pediatr. 42: 658-668, 1953).