DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

with the fully methylated ribosomal binding site is insufficient to
overcome resistance. Constitutive methylase producers can be
selected from strains with the inducible erm phenotype.
Absorption, Distribution, and Excretion.
Absorption. Erythromycin base is incompletely but adequately
absorbed from the upper small intestine. Because it is inactivated by
gastric acid, the drug is administered as enteric-coated tablets, as
capsules containing enteric-coated pellets that dissolve in the duodenum,
or as an ester. Food, which increases gastric acidity, may delay
absorption.
Peak serum concentrations are 0.3-0.5 μg/mL, 4 hours after
oral administration of 250 mg of the base, and 0.3-1.9 μg/mL after a
single dose of 500 mg. Esters of erythromycin base (e.g., stearate,
estolate, and ethylsuccinate) have improved acid stability, and their
absorption is less altered by food. A single oral 250-mg dose of erythromycin
estolate produces peak serum concentrations of ~1.5 μg/mL
after 2 hours, and a 500-mg dose produces peak concentrations of
4 μg/mL. Peak serum concentrations of erythromycin ethylsuccinate
are 1.5 μg/mL (0.5 μg/mL of base) 1-2 hours after administration of
a 500-mg dose. These peak values include the inactive ester and the
free base, the latter of which comprises 20-35% of the total. The concentration
of microbiologically active erythromycin base in serum
therefore is similar for the various preparations. Higher concentrations
of erythromycin can be achieved by intravenous administration.
Values are ~10 μg/mL 1 hour after intravenous administration of 500-
1000 mg of erythromycin lactobionate.
Clarithromycin is absorbed rapidly from the GI tract after oral
administration, but first-pass metabolism reduces its bioavailability to
50-55%. Peak concentrations occur ~2 hours after drug administration.
Clarithromycin may be given with or without food, but the
extended-release form, typically given once daily as a 1-g dose,
should be administered with food to improve bioavailability. Steadystate
peak concentrations in plasma of 2-3 μg/mL are achieved after
2 hours with a regimen of 500 mg every 12 hours, or after 2-4 hours
with two 500-mg extended-release tablets given once daily.
Azithromycin administered orally is absorbed rapidly and
distributes widely throughout the body, except to the brain and CSF.
Concomitant administration of aluminum and magnesium hydroxide
antacids decreases the peak serum drug concentrations but not overall
bioavailability. Azithromycin should not be administered with
food. A 500-mg loading dose will produce a peak plasma drug concentration
of ~0.4 μg/mL. When this loading dose is followed by
250 mg once daily for 4 days, the steady-state peak drug concentration
is 0.24 μg/mL. Azithromycin also can be administered intravenously,
producing plasma concentrations of 3-4 μg/mL after a
1-hour infusion of 500 mg.
Telithromycin is formulated as a 400-mg tablet for oral
administration. There is no parenteral form. It is well absorbed with
~60% bioavailability. Peak serum concentrations, averaging 2 μg/mL
following a single 800-mg oral dose, are achieved within 30 minutes
to 4 hours.
Distribution. Erythromycin diffuses readily into intracellular fluids,
achieving antibacterial activity in essentially all sites except the brain
and CSF. Erythromycin penetrates into prostatic fluid, achieving
concentrations ~40% of those in plasma. Concentrations in middle
ear exudate reach only 50% of serum concentrations and thus may
be inadequate for the treatment of otitis media caused by H. influenzae.
Protein binding is ~70-80% for erythromycin base and even higher,
96%, for the estolate. Erythromycin traverses the placenta, and drug
concentrations in fetal plasma are ~5-20% of those in the maternal
circulation. Concentrations in breast milk are 50% of those in serum.
Clarithromycin and its active metabolite, 14-hydroxyclarithromycin,
distribute widely and achieve high intracellular concentrations
throughout the body. Tissue concentrations generally exceed
serum concentrations. Concentrations in middle-ear fluid are 50%
higher than simultaneous serum concentrations for clarithromycin
and the active metabolite. Protein binding of clarithromycin ranges
from 40% to 70% and is concentration dependent.
Azithromycin’s unique pharmacokinetic properties include
extensive tissue distribution and high drug concentrations within
cells (including phagocytes), resulting in much greater concentrations
of drugs in tissue or secretions compared to simultaneous
serum concentrations. Tissue fibroblasts act as the natural reservoir
for the drug in vivo. Protein binding is 50% at very low plasma concentrations
and less at higher concentrations.
Telithromycin is 60-70% bound by serum protein, principally
albumin. It penetrates well into most tissues, exceeding
plasma concentrations by ~2-fold to ≥10-fold. Telithromycin is concentrated
into macrophages and white blood cells, where concentrations
of 40 μg/mL (500 times the simultaneous plasma concentration)
are maintained 24 hours after dosing.
Elimination. Only 2-5% of orally administered erythromycin is
excreted in active form in the urine; this value is from 12-15% after
intravenous infusion. The antibiotic is concentrated in the liver and
excreted in the bile, which may contain as much as 250 μg/mL when
serum concentrations are very high. The serum elimination t 1/2
of
erythromycin is ~1.6 hours. Although the t 1/2
may be prolonged in
patients with anuria, dosage reduction is not routinely recommended
in renal failure patients. The drug is not removed significantly by
either peritoneal dialysis or hemodialysis.
Clarithromycin is eliminated by renal and nonrenal mechanisms.
It is metabolized in the liver to several metabolites; the active
14-hydroxy metabolite is the most significant. Primary metabolic
pathways are oxidative N-demethylation and hydroxylation at the
14 position. The elimination half-lives are 3-7 hours for clarithromycin
and 5-9 hours for 14-hydroxyclarithromycin. Metabolism
is saturable, resulting in nonlinear pharmacokinetics with higher
dosages; longer half-lives are observed after larger doses. The
amount of clarithromycin excreted unchanged in the urine ranges
from 20% to 40%, depending on the dose administered and the formulation
(tablet versus oral suspension). An additional 10-15% of a
dose is excreted in the urine as 14-hydroxyclarithromycin. Although
the pharmacokinetics of clarithromycin are altered in patients with
either hepatic or renal dysfunction, dose adjustment is not necessary
unless the creatinine clearance is <30 mL/minute.
Azithromycin undergoes some hepatic metabolism to inactive
metabolites, but biliary excretion is the major route of elimination.
Only 12% of drug is excreted unchanged in the urine. The
elimination t 1/2
, 40-68 hours, is prolonged because of extensive tissue
sequestration and binding.
With a t 1/2
of 9.8 hours, telithromycin can be given once daily.
The drug is cleared primarily by hepatic metabolism, 50% by
CYP3A4 and 50% by CYP-independent metabolism. No adjustment
of the dose is required for hepatic failure or mild-to-moderate renal
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CHAPTER 55
PROTEIN SYNTHESIS INHIBITORS AND MISCELLANEOUS ANTIBACTERIAL AGENTS