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

110
SECTION I
GENERAL PRINCIPLES
the urine by the liver and kidney, respectively, whereas other ACE
inhibitors are excreted mainly by the kidney. The special feature of
temocapril among ACE inhibitors is that the plasma concentration of
temocaprilat remains relatively unchanged even in patients with
renal failure. However, the plasma area under the curve (AUC) of
enalaprilat and other ACE inhibitors is markedly increased in
patients with renal disorders. Temocaprilat is a bisubstrate of the
OATP family and MRP2, whereas other ACE inhibitors are not good
substrates of MRP2 (although they are taken up into the liver by the
OATP family). Taking these findings into consideration, the affinity
for MRP2 may dominate in determining the biliary excretion of any
series of ACE inhibitors. Drugs that are excreted into both the bile
and urine to the same degree thus are expected to exhibit minimum
inter-individual differences in their pharmacokinetics.
Irinotecan (CPT-11). Irinotecan hydrochloride (CPT-11) is a potent
anticancer drug, but late-onset gastrointestinal toxic effects, such as
severe diarrhea, make it difficult to use CPT-11 safely. After intravenous
administration, CPT-11 is converted to SN-38, an active
metabolite, by carboxylesterase. SN-38 is subsequently conjugated
with glucuronic acid in the liver. SN-38 and SN-38 glucuronide
are then excreted into the bile by MRP2. The inhibition of
MRP2-mediated biliary excretion of SN-38 and its glucuronide by
co-administration of probenecid reduces the drug-induced diarrhea,
at least in rats. For additional details, see Figures 6–5 and 6–7.
Angiotensin II Receptor Antagonists. Angiotensin II receptor
antagonists are used for the treatment of hypertension, acting on AT 1
receptors expressed in vascular smooth muscle, proximal tubule, and
adrenal medullary cells, and elsewhere. For most of these drugs,
hepatic uptake and biliary excretion are important factors for their
pharmacokinetics as well as pharmacological effects. Telmisartan is
taken up into human hepatocytes in a saturable manner, predominantly
via OATP1B3 (Ishiguro et al., 2006). On the other hand, both
OATPs 1B1 and 1B3 are responsible for the hepatic uptake of valsartan
and olmesartan, although the relative contributions of these
transporters are unclear. Studies using doubly transfected cells with
hepatic uptake transporters and biliary excretion transporters have
clarified that MRP2 plays the most important role in the biliary
excretion of valsartan and olmesartan.
Repaglinide and Nateglinide. Repaglinide is a meglitinide analog antidiabetic
drug. Although it is eliminated almost completely by the metabolism
mediated by CYPs 2C8 and 3A4, transporter-mediated hepatic
uptake is one of the determinants of its elimination rate. In subjects with
SLCO1B1 (gene code for OATP1B1) 521CC genotype, a significant
change in the pharmacokinetics of repaglinide was observed (Niemi
et al., 2005). Genetic polymorphism in SLCO1B1 521T>C results in
altered pharmacokinetics of nateglinide, suggesting OATP1B1 is a determinant
of its elimination, although it is subsequently metabolized by
CYPs 2C9, 3A4, and 2D6 (Zhang et al., 2006a).
Fexofenadine. Fexofenadine, a histamine H 1
receptor antagonist, is
taken up in the liver by OATP1B1 and OATP1B3 and excreted in
the bile via transporters including MRP2 and BSEP (Matsushima et
al., 2008). Patients with genetic polymorphism in SLCO1B1
521T>C, show altered pharmacokinetics.
Bosentan. Bosentan is an endothelin antagonist used to treat pulmonary
arterial hypertension. It is taken up in the liver by OATP1B1
and OATP1B3, and subsequently metabolized by CYP2C9 and
CYP3A4 (Treiber et al., 2007). Transporter-mediated hepatic uptake
can be a determinant of elimination of bosentan, and the inhibition
of hepatic uptake by cyclosporin A, rifampicin, and sildenafil can
affect its pharmacokinetics.
Drug-Drug Interactions Involving Transporter-Mediated
Hepatic Uptake. Since drug transporters are determinants
of the elimination rate of drugs from the body,
transporter-mediated hepatic uptake can be the cause of
drug-drug interactions involving drugs that are actively
taken up into the liver and metabolized and/or excreted
in the bile.
Cerivastatin (currently withdrawn), an HMG-CoA reductase
inhibitor, is taken up into the liver via transporters (especially
OATP1B1) and subsequently metabolized by CYPs 2C8 and 3A4. Its
plasma concentration is increased 1-5 fold when co-administered with
cyclosporin A. Transport studies using cryopreserved human hepatocytes
and OATP1B1-expressing cells suggest that this drug-drug
interaction is caused by inhibition of OATP1B1-mediated hepatic
uptake (Shitara et al., 2003). However, cyclosporin A inhibits the
metabolism of cerivastatin only to a limited extent, suggesting a low
possibility of serious drug-drug interactions involving the inhibition
of metabolism. Cyclosporin A also increases the plasma concentrations
of other HMG-CoA reductase inhibitors. It markedly
increases the plasma AUC of pravastatin, pitavastatin, and rosuvastatin,
which are minimally metabolized and eliminated from the body
by transporter-mediated mechanisms. Therefore, these pharmacokinetic
interactions also may be due to transporter-mediated hepatic
uptake. However, the interactions of cyclosporin A with pro-drug
statins (lactone form) such as simvastatin and lovastatin are mediated
by CYP3A4.
Gemfibrozil is another cholesterol-lowering agent that acts by
a different mechanism and also causes a severe pharmacokinetic
interaction with cerivastatin. Gemfibrozil glucuronide inhibits the
CYP2C8-mediated metabolism and OATP1B1-mediated uptake of
cerivastatin more potently than does gemfibrozil. Laboratory data
show that the glucuronide is highly concentrated in the liver versus
plasma probably owing to transporter-mediated active uptake and
intracellular formation of the conjugate. Therefore, it may be that
gemfibrozil glucuronide, concentrated in the hepatocytes, inhibits the
CYP2C8-mediated metabolism of cerivastatin. In addition, gemfibrozil
glucuronide is an inhibitor of CYP2C8. Gemfibrozil markedly
(4-5 fold) increases the plasma concentration of cerivastatin but does
not greatly increase (1.3-2 times) that of unmetabolized statins pravastatin,
pitavastatin, and rosuvastatin, a result that also suggests that this
interaction is caused by inhibition of metabolism. Thus, when an
inhibitor of drug-metabolizing enzymes is highly concentrated in hepatocytes
by active transport, extensive inhibition of the drug-metabolizing
enzymes may be observed because of the high concentration of the
inhibitor in the vicinity of the drug-metabolizing enzymes.
The Contribution of Specific Transporters to the
Hepatic Uptake of Drugs. Estimating the contribution
of transporters to the total hepatic uptake is necessary
for understanding their importance in drug disposition.