Pharmacokinetics for
macrolides
Macrolides are a class
of broad spectrum antibiotics of large molecular size. The class
includes erythromycin, clarithromycin, and azithromycin, among
others
Pharmacokinetics deals
with the action of the drug in the body over a period of time,
encompassing issues of absorption, distribution, metabolism, and
elimination.
- The pharmacokinetic
properties of macrolide antibiotics differ based on their chemical
structure. In low pH environments, such as in the stomach,
erythromycin is degraded
- Macrolides work
by binding
to a specific subunit of ribosomes in susceptible bacteria, thereby
inhibiting the formation of bacterial proteins. In most organisms
this action inhibits cell growth; however, in high concentrations
it can cause cell death.
- The
8,9-anhydro-6,9-hemiketal intermediate is inactive as an antibiotic
but may cause the gastrointestinal adverse effects that have been
associated with erythromycin.
- This intermediate is
then further metabolized into the inactive anhydroerythromycin,
erythromycin-6,9;9,12-spiroketal.
- Clarithromycin is more
acid-stable than erythromycin and is not degraded as extensively in
the stomach.
- Azithromycin is even
more stable at low pH, resulting in a longer serum half-life and
increased concentrations in tissues compared to
erythromycin.
- As a result of their
better stability at low pH, azithromycin has an oral
bioavailability of 37% and clarithromycin has an oral
bioavailability of 55%, compared to an oral bioavailability of 25%
for erythromycin.
- Peak serum
concentrations of azithromycin and clarithromycin are lower than
for erythromycin of the same dose.
- Macrolide absorption in
the intestine is limited by P-glycoprotein efflux
transporters.
- Macrolides are
lipophilic and are widely distributed in blood and tissues. Once in
the bloodstream, macrolides preferentially bind alpha-1-acid
glycoprotein, the binding protein found in the highest
concentration after albumin.
- Macrolides concentrate
in phagocytes, which then transport the drug to the site of
infection. Concentrations in phagocytes of clarithromycin and
azithromycin are 400 times and 800 times that of what is found in
the serum.
- The macrolides
are inactivated in the liver, and the major route of elimination is
in the bile. They have low toxicity, and serious untoward effects
are rarely encountered.
Pharmacokinetics for
Aminoglycosides
Aminoglycosides are
neither protein bound nor biotransformed. The major route of
elimination is glomerular filtration, and aminoglycosides undergo
some tubular reabsorption.
Aminoglycosides
are the
mainstay in the treatment of serious gram negative infections
including catheter-associated infections.
- They are not
metabolized and are rapidly excreted as such by glomerular
filtration resulting in a plasma t½ of approximately two
hours in those with normal renal function.
- Inhibition of protein
synthesis. Once inside the bacterial cell, aminoglycosides
bind to the 30s ribosomal sub-unit and cause a misreading of the
genetic code.
- This subsequently leads
to the interruption of normal bacterial protein
synthesis.
- Due to the almost
exclusive excretion from the body by glomerular filtration, the
elimination rate of aminoglycoside antibiotics is greatly affected
by impairment of renal function.
- In the neonatal period,
the absorption rate after intramuscular injection appears to be
faster than reported in adults and the volume of distribution is
significantly larger.
- The major
pharmacokinetic difference between neonates, infants and adults is
the slower elimination: for instance, half-lives which average
around 2 hours in adults with normal renal function can reach and
sometimes exceed 5 to 6 hours during the very first days of
life.
Pharmacokinetics
for Tetracyclines and Glycopeptide
Antibiotics
Tetracyclines are a
class of broad-spectrum antibiotics used in the management
and treatment of a variety of infectious diseases. Naturally
occurring drugs in this class are tetracycline, chlortetracycline,
oxytetracycline, and demeclocycline.
Glycopeptide
antibiotics include the anti-infective antibiotics
vancomycin, teicoplanin, telavancin, ramoplanin and decaplanin,
corbomycin, complestatin and the antitumor antibiotic
bleomycin.
In general the
tetracyclines can be divided into three groups based on their
pharmacokinetic and antibacterial properties.
Group 1:
This group consists of the older agents which have reduced
absorption and are less lipophilic than newer drugs in group
2.
- Examples are
tetracycline, oxytetracycline, chlortetracycline, demeclocycline
(demethyl chlorotetracycline), lymecycline, methacycline and
rolitetracycline. All can be administered orally except for
rolitetracycline.
- Absorption is variable
ranging from 0% to almost 90%; however, for most agents it is in
the range 25–60%.
- Serum concentrations
rise slowly after oral administration with absorption occurring in
the stomach, duodenum and small intestine.
Cmax (mg/L) depends on dose, but is generally
in the range 1–5 mg/L
Group 2:
These drugs are more or less completely absorbed and are 3–5 times
more lipophilic than drugs in group 1.
- This may improve their
tissue distribution but convincing data is absent. They are
available in oral and intravenous formulations. Examples are
doxycycline and minocycline.
- Doxycycline is said to
be almost completely absorbed with a bioavailability of more than
80% with an average of ∼95%.
- Absorption takes place
in the duodenum.
- The half-life of
absorption is 0.85 ± 0.41 h.
- The peak concentration
(Cmax, mg/L) varies with dose being 15.3
mg/L 4 h after a dose of 500 mg orally
Group 3:
This group includes the developmental compounds
aminomethylcyclines.
- These antibiotics are
active in vitro against many bacteria with acquired resistance to
tetracyclines.
- There are no data on
absorption of tigecycline, but its oral bioavailability is reported
to be limited.
- A light
breakfast did not have a significant effect on iv tigecycline
pharmacokinetics.
- The volume of
distribution is large with initial values of volume of distribution
at steady state (Vss) being >10 L/kg.
Total volumes of distribution are ∼350 L in women and 500
L in men.