Biomedical Engineering Reference
In-Depth Information
are described as OATP inhibitors.
122
Recently, troglitazone sulfate, the metabolite of
troglitazone (an insulin-sensitizing drug developed for the treatment of type 2 diabetes
mellitus) as well as other thiazolidinediones (e.g., pioglitazone and rosiglitazone) have
been demonstrated to inhibit OATP1B1 and/or OATP1B3 in vitro, thus suggesting a
possible involvement of troglitazone sulfate in troglitazone hepatotoxicity, the rare
side effect that caused withdrawal of the drug from the market.
613
Finally, in in vitro studies, several Pgp substrates and inhibitors were shown to
inhibit OATP transport activity to various extents. The HMG-CoA reductase inhibitor
lovastatin and the HIV-1 protease inhibitors ritonavir, saquinavir, and nelfinavir, as
well as quinidine, ketoconazole, and verapamil,
122
were reported to reduce OATP-
mediated transport activity.
Inducers
Several studies have demonstrated that OATP expression can be induced by
various compounds that are well-known ligands and activators of the nuclear receptors
pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Furthermore,
the expression of certain OATPs (such as OATP1B1 and OATP1B3) has been sug-
gested to be under transcriptional control by hepatocyte nuclear factor 1
).
Indeed, in a recent study, rat Oatp1b1 expression was shown to be modulated by
several classes of drug-metabolizing enzyme inducers. In particular, Oatp1b1 expres-
sion was increased moderately by CAR ligands and increased dramatically by PXR
ligands: phenobarbital, diallyl sulfide, and polychlorinated biphenyl were reported
to increase Oatp1b1 expression. Other compounds, such as spironolactone, dexam-
ethasone, and diethylhexylphthalate, were shown to enhance Oatp1b1 expression by
a different mechanism.
614
Previous studies in humans revealed that the barbiturate phenobarbital increased
the hepatic clearance of organic anions BSP and bilirubin from plasma.
615
In pre-
clinical studies, phenobarbital treatment enhanced the transport maximum for the
excretion of bilirubin into bile in rats and significantly stimulated (more than sixfold)
the maximum uptake velocity of BSP in isolated rat hepatocytes.
616
,
617
Analogously,
pretreatment of rats with phenobarbital and the synthetic steroid pregnenolone-16
(NF1
-
carbonitril resulted in a reduced plasma half-life, increased hepatic clearance, and
decreased toxicity of certain cardiac glycosides (e.g., digoxin, digitoxin, ouabain)
that are well-known OATP substrates.
618
-
620
Increased hepatic uptake of cardiac gly-
cosides by the two compounds was also induced in isolated hepatocytes.
621
More
recently, phenobarbital and pregnenolone-16a-carbonitril were shown to enhance
the expression of Oatp1B1 in rats, and consequently, the uptake of digoxin was
increased.
403
However, in primary human and mouse hepatocytes, phenobarbital de-
creased OATP1B3, OATP2B1, and Oatp1a1 mRNA expression, respectively.
622
,
623
These findings support the hypothesis that modulation of Oatp/OATP expression in
rats, as well as in humans, by phenobarbital and other compounds may affect the
pharmacokinetics of coadministered OATP substrate drugs, leading to potentially
clinically relevant drug-drug interactions.
624
-
626
On the other hand, as the hepatic
expression of OATP1B3 has been reported to depend on hepatocyte nuclear fac-
tor 1
(HNF1
) and on the bile acid nuclear receptor farnesoid X-activated receptor
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