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

998 complex with both the reduced and oxidized enzyme and inhibits
catalytic function in both states.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Absorption, Distribution, and Elimination. Febuxostat is rapidly
absorbed with maximum plasma concentrations between 1-1.5 hours
post-dose. The absorption of radiolabeled compound was estimated
to be at least 49%, however, the absolute bioavailability is unknown.
Magnesium hydroxide and aluminum hydroxide delay absorption
~1 hour. Food reduces absorption slightly, but has no clinically significant
effect on the reduction of serum uric acid concentration.
Febuxostat is highly plasma protein bound and has a volume of distribution
of 50 L. It is extensively metabolized by oxidation by CYPs
1A2, 2C8, and 2C9 and non-CYP enzymes conjugation via UGTs
1A1, 1A3, 1A9 and 2B7. The relative contribution of each metabolic
route is not known. The oxidation of the isobutyl side chain leads to
the formation of four pharmacologically active hydroxy metabolites,
all of which occur in plasma at markedly lower concentrations than
febuxostat. Febuxostat has a t 1/2
of 5-8 hours and is eliminated by
both hepatic and renal pathways. Mild to moderate renal or hepatic
impairment does not affect its elimination kinetics relevantly.
Therapeutic Use. Febuxostat (ULORIC; ADNEURIC [EUROPE]) is
approved for hyperuric patients with gout attacks, but not recommended
for treatment of asymptomatic hyperuricemia. It is available
in 40 and 80-mg oral tablets. Three randomized controlled
clinical trials that compared febuxostat with allopurinol showed
that 40 mg/day febuxostat lowered serum uric acid to similar levels as
300 mg/day allopurinol. More patients reached the target concentration
of 6.0 mg/dL (360 μmol/L) on 80 mg/day febuxostat than on
300 mg/day allopurinol (Becker et al., 2005a; Becker et al., 2005b;
Schumacher et al., 2008). Thus, therapy should be initiated with
40 mg/day and the dose increased if the target serum uric acid concentration
is not reached within 2 weeks.
Common Adverse Events. The most common adverse reactions in
clinical studies were liver function abnormalities, nausea, joint pain,
and rash. Liver function should be monitored periodically. An
increase in gout flares was frequently observed after initiation of
therapy, due to reduction in serum uric acid levels resulting in mobilization
of urate from tissue deposits. Concurrent prophylactic treatment
with an NSAID or colchicine is usually required. There was
also a numerically higher rate of myocardial infarction and stroke
in patients on febuxostat than on allopurinol. It is currently unknown
whether there is a causal relationship between the cardiovascular
events and febuxostat therapy or whether these were due to chance.
The FDA has imposed as a condition for approval that a prospective
study designed to assess the drug’s cardiovascular safety be performed.
Meanwhile patients should be monitored for cardiovascular
complications.
Drug Interactions. Plasma levels of drugs that are metabolized by
xanthine oxidase (e.g., theophylline, mercaptopurine, azathioprine)
can be expected to increase—possibly to toxic levels—when administered
concurrently with febuxostat, although drug interaction studies
with these drugs have not been conducted. Thus, febuxostat is
contraindicated in patients on azathioprine, mercaptopurine, or theophylline.
Based on in vitro studies, interactions between febuxostat
and CYP inhibitors are likely, but interactions studies have not been
performed in humans.
Rasburicase
Rasburicase (ELITEK) is a recombinant urate oxidase
that catalyzes the enzymatic oxidation of uric acid into
the soluble and inactive metabolite allantoin. It has been
shown to lower urate levels more effectively than allopurinol
(Bosly et al., 2003). It is indicated for the initial
management of elevated plasma uric acid levels in pediatric
patients with leukemia, lymphoma, and solid
tumor malignancies who are receiving anticancer therapy
expected to result in tumor lysis and significant
hyperuricemia.
Produced by a genetically modified Saccharomyces cerevisiae
strain, the therapeutic efficacy may be hampered by the production
of antibodies against the drug. Hemolysis in
glucose-6-phosphate dehydrogenase (G6PD)-deficient patients,
methemoglobinemia, acute renal failure, and anaphylaxis have been
associated with the use of rasburicase. Other frequently observed
adverse reactions include vomiting, fever, nausea, headache, abdominal
pain, constipation, diarrhea, and mucositis. Rasburicase causes
enzymatic degradation of the uric acid in blood samples, and special
handling is required to prevent spuriously low values for plasma uric
acid in patients receiving the drug. The recommended dose of rasburicase
is 0.15 mg/kg or 0.2 mg/kg as a single daily dose for 5 days,
with chemotherapy initiated 4-24 hours after infusion of the first rasburicase
dose.
Uricosuric Agents
Uricosuric agents increase the rate of excretion of uric
acid. In humans, urate is filtered, secreted, and reabsorbed
by the kidneys. Reabsorption predominates,
such that the net the amount excreted usually is ~10%
of that filtered. Reabsorption is mediated by an organic
anion transporter family member, URAT-1, which can
be inhibited. A number of other organic acid transporters,
may also participate in urate exchange at the
basolateral membrane of proximal tubule epithelial
cells (Terkeltaub et al., 2006).
URAT-1 exchanges urate for either an organic anion such as
lactate or nicotinate or less potently for an inorganic anion such as
chloride. The monocarboxylate metabolite of the anti-tuberculous
drug pyrazinamide, an organic anion, is a potent stimulator of urate
reuptake. Uricosuric drugs such as probenecid, sulfinpyrazone,
benzbromarone, and losartan compete with urate for the transporter,
thereby inhibiting its reabsorption via the urate–anion exchanger system.
However, transport is bidirectional, and depending on dosage,
some drugs, including salicylates, may either decrease or increase
the excretion of uric acid. Decreased excretion usually occurs at a
low dosage, while increased excretion is observed at a higher dosage.
Not all agents show this phenomenon, and one uricosuric drug may
either add to or inhibit the action of another.
Two mechanisms for a drug-induced decrease in urinary excretion
of urate have been advanced; they are not mutually exclusive. The