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

Extracellular space
Mannoprotein
Glucan
Chitin
Glucan synthase
complex
Cell wall
Periplasm
Plasma membrane
Cytoplasm
Echinocandin
anti-fungal
Figure 57–3. The fungal cell wall and membrane and the action of echinocandins. The strength of the fungal cell wall is maintained
by fibrillar polysaccharides, largely β-1,3-glucan and chitin, which bind covalently to each other and to proteins. A glucan synthase
complex in the plasma membrane catalyzes the synthesis of beta-1,3-glucan; the glucan is extruded into the periplasm and incorporated
into the cell wall. Echinocandins inhibit the activity of the glucan synthase complex, resulting in loss of the structural integrity
of the cell wall. A subunit of glucan synthase designated Fks1p is thought to be the target of the echinocandin. Mutations in Fks1p,
coded for by FSK1, cause resistance to echinocandins.
as Histoplasma capsulatum. Echinocandins have no activity against
Cryptococcus neoformans, Trichosporon spp., or agents of
mucormycosis. In vitro studies have consistently failed to show synergism
or antagonism between echinocandins and amphotericin B.
There is no antagonism between echinocandins and azoles; an additive
effect has been reported with Aspergillus in some in vitro systems
and animals models. Echinocandin resistance can be selected
in Candida albicans under drug pressure both in vitro and clinically
during prolonged echinocandin therapy. Resistance is from mutations
in a conserved region of the FKS1 gene, coding for amino acids
Phe 641 -Asp 658 (Park et al., 2005). FKS1p is an essential component
of the 1,3-β-D-glucan synthase complex (Figure 57–3).
Caspofungin
Caspofungin acetate (CANCIDAS) is a water-soluble,
semisynthetic lipopeptide synthesized from the fermentation
product of Glarea lozoyensis (Johnson and
Perfect, 2003; Keating and Figgit, 2003).
Table 57-7
Pharmacokinetics of Echinocandins in Humans
DRUG DOSE (mg) C max
(μg/mL) AUC 0-24h
(mg•h/L) t 1/2
(h) Cl (mL/min/kg) V d
(L)
Caspofungin 70 12 93.5 10 0.15 9.5
Micafungin 75 7.1 59.9 13 0.16 14
Anidulafungin 200 7.5 104.5 25.6 0.16 33.4
For details, see Wagner et al. (2006).