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

CL int,all
PS 1
PS 2
CL met
Metabolic
enzymes
PS 3
bile
blood
Figure 5–10. Diagram showing hepatic uptake, backflux into
blood, metabolism, and efflux into bile. The red circles represent
parent drugs; the green triangles represent drug metabolites. PS,
permeability surface product; CL met
, metabolic clearance; CL int
,
intrinsic clearance.
for determining drug exposure in the circulating blood
and liver. Moreover, there are many other uptake and
efflux transporters in the liver (Figures 5–10 and 5–11).
The following examples illustrate the importance of
vectorial transport in determining drug exposure in the
circulating blood and liver.
HMG-CoA Reductase Inhibitors. Statins are cholesterol-lowering
agents that reversibly inhibit HMG-CoA reductase, which catalyzes
a rate-limiting step in cholesterol biosynthesis (see Chapter 31).
Statins affect serum cholesterol by inhibiting cholesterol biosynthesis
in the liver, and this organ is their main target. On the other hand,
exposure of extrahepatic cells in smooth muscle to these drugs may
cause adverse effects. Among the statins, pravastatin, fluvastatin,
cerivastatin, atorvastatin, rosuvastatin, and pitavastatin are given in
a biologically active open-acid form, whereas simvastatin and lovastatin
are administered as inactive prodrugs with lactone rings. The
open-acid statins are relatively hydrophilic and have low membrane
permeabilities. However, most of the statins in the acid form are substrates
of uptake transporters, so they are taken up efficiently by the
liver and undergo enterohepatic circulation (Figures 5–5 and 5–11).
In this process, hepatic uptake transporters such as OATP1B1 and
efflux transporters such as MRP2 act cooperatively to produce vectorial
trans-cellular transport of bisubstrates in the liver. The efficient
first-pass hepatic uptake of these statins by OATP1B1 after their oral
administration helps to exert the pharmacological effect and also
minimizes the escape of drug molecules into the circulating blood,
thereby minimizing the exposure in a target of adverse response,
smooth muscle. Recent studies indicate that the genetic polymorphism
of OATP1B1 also affects the function of this transporter
(Tirona et al., 2001).
Temocapril. Temocapril is an ACE inhibitor (see Chapter 26). Its
active metabolite, temocaprilat, is excreted both in the bile and in
109
CHAPTER 5
MEMBRANE TRANSPORTERS AND DRUG RESPONSE
MRP1
(ABCC1)
MRP3
(ABCC3)
MRP4
(ABCC4)
Blood
OATP1B1
(OATP2/OATP-C)
MDR3
(ABCB4)
OATP1B3
(OATP8)
MDR1
(ABCB1)
OATP2B1
(OATP-B)
MDP2
(ABCC2)
Bile
canaliculus
OAT2
OCT1
NTCP
Sinusoidal
membrane
BCRP
(ABCG2)
BSEP
(ABCB11)
Canalicular
membrane
Figure 5–11. Transporters in the hepatocyte that function in the uptake and efflux of drugs across the sinusoidal membrane and
efflux of drugs into the bile across the canalicular membrane. See text for details of the transporters pictured.