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

mRNA
30S
Mycobacterium
RNA Polymerase
DNA
P i
ADP
under the concentration-time curves (AUC) with repeated administration
(Table 56–3). They have good penetration into many tissues,
but levels in the CNS reach only ~5% of those in plasma, likely due
to the activity of P-glycoprotein. The drugs and metabolites are
excreted by bile and eliminated via feces, with urine elimination
accounting for only one-third and less of metabolites.
The population pharmacokinetics (PK) of rifampin are best
described using a one-compartment model with transit compartment
absorption (Wilkins et al., 2008), using the PK parameters in Table
56–2. Single-drug formulations increase mean transit time during
absorption by ~100% and systemic clearance (SCL) by 24% in
comparison to fixed-dose combinations of rifampin and other anti-
TB drugs. Thus the absorption of rifampin will be slower, and the
peak concentration (C Pmax
) of rifampin lower, with some formulations
compared to others (Wilkins et al., 2008).
Rifapentine pharmacokinetics are likewise best described
using a one-compartment open model with first-order absorption and
elimination (Langdon et al., 2005). The PK parameters are summarized
in Table 56–2. However, for each 1-kg weight increase above
50 kg, SCL increases by 0.05 L/hour and V d
by 0.69 L. Thus, C Pmax
and AUC decrease with increasing patient weight above 50 kg.
H +
Approved Drugs
Fluoroquinolone:
inhibits DNA synthesis and supercoiling by
targeting topoisomerase
Rifamycin:
inhibits RNA synthesis by targeting RNA polymerase
Streptomycin:
inhibits protein synthesis by targeting the 30S
ribosomal subunit
Macrolides:
target 23S ribosomal RNA, inhibiting
peptidyl transferase
a
b
a
ATP
ATP
synthase
Mycolic
acid
Isoniazid and Ethionamide:
inhibit mycolic acid synthesis
Ethambutol:
inhibits cell wall synthesis
Pyrazinamide:
inhibits cell membrane synthesis
Cell wall
Cell membrane
Experimental Drugs
TMC-207 (R207910, TMC):
inhibits ATP synthase
PA-824:
inhibits mycolic acid and protein biosynthesis;
possibly acts via generation of toxic radicals
Figure 56–1. Mechanisms of action of established and experimental drugs used for the chemotherapy of mycobacterial infections. Shown
at the top are the sites of action of approved drugs for the chemotherapy of mycobacterial diseases. Rifamycin is used as a generic
term for several drugs, of which rifampin is used most frequently. Also included are two experimental drugs now under investigation:
TMC-207 and PA-824. Clofazimine, whose mode of action is not understood, is omitted.
Rifabutin pharmacokinetics are best described by a twocompartment
open model with first-order absorption and elimination.
Rifabutin disposition is biexponential. Rifabutin concentrations
are substantially higher in tissue than in plasma due to its lipophilic
properties, leading to the very high apparent volumes of distribution
(Table 56–2). The consequence is that C Pmax
values for rifabutin are
lower than one would predict by comparison with other rifamycins.
The volume of peripheral compartment decreases by 27% with concomitant
azithromycin administration; tobacco smoking increases
the volume by 39%.
Pharmacokinetics-Pharmacodynamics. Rifampin’s bactericidal
activity is best optimized by a high AUC/MIC
ratio (Gumbo et al., 2007a). However, resistance suppression
and rifampin’s enduring post-antibiotic effect
are best optimized by high C max
/MIC. Therefore, the
duration of time that the rifampin concentration persists
above the MIC is of less importance.
These results predict that the t 1/2
of a rifamycin is less of an issue
in optimizing therapy, and that if patients could tolerate it, higher doses
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CHAPTER 56
CHEMOTHERAPY OF TUBERCULOSIS, MYCOBACTERIUM AVIUM COMPLEX DISEASE, AND LEPROSY