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

compared with wild-type mice, although the plasma concentrations
of metformin are similar in the wild-type and knockout mice. These
results indicate that the OCT1-mediated hepatic uptake of biguanides
plays an important role in lactic acidosis (Wang et al., 2003).
The organic anion transporter 1 (OAT1) and organic cation
transporters (OCT1 and OCT2) provide other examples of transporterrelated
toxicity. OAT1 is expressed mainly in the kidney and is responsible
for the renal tubular secretion of anionic compounds. Substrates of
OAT1, such as cephaloridine (a β-lactam antibiotic), and adefovir and
cidofovir (antiviral drugs), reportedly cause nephrotoxicity. In vitro
experiments suggest that cephaloridine, adefovir, and cidofovir are substrates
of OAT1 and that OAT1-expressing cells are more susceptible to
the toxicity of these drugs than control cells (Ho et al., 2000; Takeda
et al., 1999). Exogenous expression of OCT1 and OCT2 enhances the
sensitivities of tumor cells to the cytotoxic effect of oxaliplatin for
OCT1, and cisplatin and oxaliplatin for OCT2 (Zhang et al., 2006b).
Drugs may modulate transporters for endogenous ligands and
thereby exert adverse effects (Figure 5–3, bottom panel). For example,
bile acids are taken up mainly by Na + -taurocholate cotransporting
polypeptide (NTCP) (Hagenbuch et al., 1991) and excreted into
the bile by the bile salt export pump (BSEP, ABCB11) (Gerloff
et al., 1998). Bilirubin is taken up by OATP1B1 and conjugated with
glucuronic acid, and bilirubin glucuronide is excreted by the multidrugresistance-associated
protein (MRP2, ABCC2). Inhibition of these
transporters by drugs may cause cholestasis or hyperbilirubinemia.
Troglitazone, a thiazolidinedione insulin-sensitizing drug used for
the treatment of type II diabetes mellitus, was withdrawn from the
market because it caused hepatotoxicity. The mechanism for this
troglitazone-induced hepatotoxicity remains unclear. One hypothesis
is that troglitazone and its sulfate conjugate induced cholestasis.
Troglitazone sulfate potently inhibits the efflux of taurocholate (K i
=
0.2 μM) mediated by the ABC transporter BSEP. These findings suggest
that troglitazone sulfate induces cholestasis by inhibition of
BSEP function. BSEP-mediated transport is also inhibited by other
drugs, including cyclosporin A and the antibiotics rifamycin and
rifampicin (Stieger et al., 2000).
Thus, uptake and efflux transporters determine
the plasma and tissue concentrations of endogenous
compounds and xenobiotics, and thereby can influence
the systemic or site-specific toxicity of drugs.
BASIC MECHANISMS OF
MEMBRANE TRANSPORT
Transporters Versus Channels. Both channels and transporters
facilitate the membrane permeation of inorganic
ions and organic compounds (Reuss, 2000). In general,
channels have two primary states, open and closed, that
are totally stochastic phenomena. Only in the open state do
channels appear to act as pores for the selected ions, allowing
their permeation across the plasma membrane. After
opening, channels return to the closed state as a function
of time. In contrast, a transporter forms an intermediate
complex with the substrate (solute), and subsequently a
conformational change in the transporter induces translocation
of the substrates to the other side of the membrane.
Therefore, there is a marked difference in turnover rates
between channels and transporters. The turnover rate constants
of typical channels are 10 6 to 10 8 s –1 , whereas those
of transporters are, at most, 10 1 to 10 3 s –1 . Because a
particular transporter forms intermediate complexes with
specific compounds (referred to as substrates), transportermediated
membrane transport is characterized by saturability
and inhibition by substrate analogs, as described in
“Kinetics of Transport.”
The basic mechanisms involved in solute transport
across biological membranes include passive diffusion,
facilitated diffusion, and active transport. Active transport
can be further subdivided into primary and secondary
active transport. These mechanisms are depicted in
Figure 5–4 and described in the next sections.
Passive Diffusion. Simple diffusion of a solute across
the plasma membrane consists of three processes: partition
from the aqueous to the lipid phase, diffusion
across the lipid bilayer, and repartition into the aqueous
phase on the opposite side. Diffusion of any solute
(including drugs) occurs down an electrochemical
potential gradient of the solute.
Such diffusion may be described by the equation:
(Equation 5–1)
where Δμ is the potential gradient, z is the charge valence of the
solute, E m
is the membrane voltage, F is the Faraday constant, R is
the gas constant, T is the absolute temperature, C is the concentration
of the solute inside (i) and outside (o) of the plasma membrane. The
first term on the right side in Equation (5–1) represents the electrical
potential, and the second represents the chemical potential.
For non-ionized compounds, the flux J owing to simple diffusion
is given by Fick’s first law (permeability multiplied by the
concentration difference). For ionized compounds, the difference in
electrical potential across the plasma membrane needs to be taken
into consideration. Assuming that the electrical field is constant, the
flux is given by the Goldman-Hodgkin-Katz equation:
J =−
⎛ C ⎞
i
Δ μ = zE F + RT In
m ⎜ ⎟
⎝ C o ⎠
P zE F
RT
⎡ C − C exp E F / RT
⎢
− exp( E F RT
⎣⎢
1
/
m )
m i o m
( )
(Equation5–2)
where P represents the permeability. The lipid and water solubility
and the molecular weight and shape of the solute are determinants of
⎤
⎥
⎦⎥
93
CHAPTER 5
MEMBRANE TRANSPORTERS AND DRUG RESPONSE