Current Concepts in Drug Metabolism and Toxicology

Visit the link below to download the full version of this book:

https://medipdf.com/product/current-concepts-in-drug-metabolism-and-toxicology-2
/

Click Download Now

 Contributors xi

B. K. Park (207) MRC Centre for Drug Safety Science; and Stem Cells for
Safer Medicine, Department of Molecular and Clinical Pharmacology,
University of Liverpool, Liverpool, United Kingdom
Marija Popovic (81) Department of Pharmaceutical Sciences, Leslie Dan
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Current address: Non-Clinical Safety Assessment, Eli Lilly & Co.,
Indianapolis, IN, USA
C. Rowe (207) MRC Centre for Drug Safety Science; and Stem Cells for
Safer Medicine, Department of Molecular and Clinical Pharmacology,
University of Liverpool, Liverpool, United Kingdom
Amy Sharma (81) Department of Pharmaceutical Sciences, Leslie Dan
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Edith Sim (169) Department of Pharmacology, University of Oxford,
Mansfield Road, Oxford; and Faculty of Science, Engineering and
Computing, Kingston University, Kingston, United Kingdom
R. L. C. Sison-Young (207) MRC Centre for Drug Safety Science; and Stem
Cells for Safer Medicine, Department of Molecular and Clinical
Pharmacology, University of Liverpool, Liverpool, United Kingdom
Tadatoshi Tanino (81) Department of Pharmaceutical Sciences, Leslie Dan
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Current address: Faculty of Pharmacy, Kinki University, Osaka, Japan
Jack Uetrecht (81) Department of Pharmaceutical Sciences, Leslie Dan
Faculty of Pharmacy; and Department of Pharmacology and Toxicology,
Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Rob Webster (257) Pfizer Global Research and Development, Sandwich,
Kent, United Kingdom
Xiaochu Zhang (81) Department of Pharmaceutical Sciences, Leslie Dan
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Xu Zhu (81) Department of Pharmaceutical Sciences, Leslie Dan Faculty of
Pharmacy, University of Toronto, Toronto, Ontario, Canada
 J. P. Keogh
Independent DMPK Consultant, Hitchin, Hertfordshire, United Kingdom
(formerly Mechanisms and Extrapolations Technologies, Drug Metabolism and
Pharmacokinetics, GlaxoSmithKline, R&D Ltd.)

Membrane Transporters in Drug

Development

Abstract 

Membrane transporters have wide, but specific tissue distributions. They

can impact on multiple endogenous and xenobiotic processes. Knowledge
and awareness within the pharmaceutical industry of their impact on drug
absorption, distribution, metabolism and elimination (ADME) and drug
safety is growing rapidly. Clinically important transporter-mediated drug–
drug interactions (DDIs) have been observed. Up to nine diverse transporters
are implicated in the DDIs of a number of widely prescribed drugs, posing a
significant challenge to the pharmaceutical industry. There is a complex
interplay between multiple transporters and/or enzymes in the ADME and
pharmacogenomics of drugs. Integrating these different mechanisms to
understand their relative contributions to ADME is a key challenge.
Many different factors complicate the study of membrane transporters
in drug development. These include a lack of specific substrates and inhibi-
tors, non-standard in vitro tools, and competing/complementary mecha-
nisms (e.g. passive permeability and metabolism).
Discovering and contextualizing the contribution of membrane trans-
porters to drug toxicity is a significant new challenge.
Drug interactions with key membrane transporters are routinely
assessed for central nervous system (CNS) drug discovery therapies, but are
not generally considered across the wider drug discovery. But, there is inter-
est in utilizing membrane transporters as drug delivery agents.
Computational modeling approaches, notably physiology-based/phar-
macokinetic (PB/PK) modeling are increasingly applied to transporter inter-
actions, and permit integration of multiple ADME mechanisms. Because of
the range of tissues and transporters of interest, robust transporter, in vitro
Advances in Pharmacology, Volume 63 1054-3589/12 $35.00
© 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/B978-0-12-398339-8.00001-X
2     J. P. Keogh

to in vivo, scaling factors are required. Empirical factors have been applied,
but absolute protein quantitation will probably be required.

I. Introduction 

A. What are Drug Transporters?

Compartmentalization at intracellular, cellular and tissue levels is fun-
damental to the function and well being of living organisms. Higher organ-
isms contain a complex system of physical barriers, which help to control
systemic, tissue and cellular exposure to both xenobiotics and endogenous
molecules. Specific mechanisms have evolved which selectively absorb nutri-
ents and excrete waste products across these barriers, and to ensure that
endogenous substances are maintained at normal levels in the body. These
same systems can also modulate the absorption, distribution, metabolism
and elimination (ADME) of xenobiotic substances. Molecules with a net
charge (positive or negative) will have restricted access to cells and tissues,
unless facilitated by uptake transporters, because of their inability to cross
the plasma membrane. Conversely highly permeable molecules should gen-
erally have good penetration, unless restricted by the activity of efflux trans-
porters. Most endogenous molecules exist as charged species. Small changes
in pH, differences in protein binding and/or relative solubility between
extra- and intracellular milieu may also influence the net concentrative effect
of a transporter. Both uptake and efflux transporters are present in most, if
not all, cell types. Whilst the overall transporter complement will influence
intracellular drug concentrations, their effects may also be quite subtle. The
fundamental action of a membrane transporter protein is either to maintain
a substrate in equilibrium, or to establish a concentration gradient across a
membrane, or tissue barrier, which could not otherwise be achieved.
There are approximately 400 transporter-like genes expressed in
humans. These are categorized into two major superfamilies: the solute car-
rier (SLC) (Heddiger, 2010) and ATP-binding cassette (ABC) transporters
(Muller, 2006). The ABC superfamily is significantly smaller (48 members)
than the SLC (over 300 members). Both superfamilies are further catego-
rized, based on similarity of function and/or gene sequence. Both transporter
superfamilies appear to have broad substrate specificities, ranging from
metal ion transport, bile salts, sugars, hormones, amino and nucleic acids,
small peptides and nucleosides, and of course, xenobiotics. All the ABC and
many of the SLC transporters behave as active transporters. It is convenient
to think of ABC transporters as maintainers of low intracellular concentra-
tion of their substrates (i.e. efflux transporters), and SLC transporters as
establishers of high intracellular concentrations (i.e. uptake transporters),
but there are exceptions. ABC transporters (e.g. P-glycoprotein, also referred
 Membrane Transporters in Drug Development      3

to as Pgp or MDR1) directly hydrolyze ATP, SLC transporters create con-

centration gradients by co-transport and/or exchange of ions, or act as facil-
itative transporters. Although it is generally accepted that Pgp (and perhaps
other ABC transporters) takes its substrates from the plasma membrane,
and solute transporters from the free fraction in the blood or cytosol, crystal
structures are not available and so the precise mechanisms involved are still
a matter of investigation.

II. Key Features of Transporters 

A. Location, Orientation, and Function

Membrane transporters are membrane bound proteins with multiple
trans-membrane spanning domains and specific cellular locations and mem-
brane orientations, which define their tissue/cellular function. Knowledge of
transporter tissue distribution and cellular localization is essential if one is
to understand the role of a particular transporter in a given organ or cell.
For example, Pgp is a luminally expressed efflux transporter. It is widely
expressed in tissues, most notably in the gastrointestinal tract (GIT), liver,
brain and kidney. As an efflux transporter, it maintains low intracellular
concentrations of its substrates. In the GIT and central nervous system
(CNS), Pgp effluxes molecules into the gut lumen or into the blood, limiting
cellular exposure, oral absorption or CNS exposure to drugs, and protecting
the body and CNS from significant exposure. By contrast, in the kidney and
liver, Pgp expels its substrates (in this instance already present in the cell)
into the urine and bile.
Transporters are also differentially distributed across tissues and organs.
For instance OATP1B1 and OATP1B3 are essentially specific to the liver,
whereas OATP4C1 is specific to the kidney. However, other transporters
have a far more widespread distribution, e.g. Pgp, OCT3, and MRP4 (Fig. 1).

B. Differential Distribution and Interplay/Redundancy

There is interplay between efflux and uptake transporters, which depend
on their differential distribution in the cell, tissue or physiological location.
Many drugs are substrates and/or inhibitors of multiple transporters. Some
scenarios are outlined below:
1. Same cell surface location, different function: both uptake and efflux
transporters with similar substrate specificities can be located on the
same cell surface. For example, the organic anion efflux transporters
MRP3 and MRP4 and organic anion uptake transporters OATP1B1 and
OATP1B3 are all expressed on the sinusoidal surface of hepatocytes. The
relative affinities, local substrate concentrations, and relative expression
4     J. P. Keogh

FIGURE 1 Schematic (not comprehensive) illustrating the extensive distribution of mem-

brane transporters in vivo, and their basic function in each tissue. The precise cellular localiza-
tion will also impact on net effect in the organ.

levels of these complementary transporters will influence the net impact

on the intracellular and extracellular concentration of a given co-­
substrate, such as bile salts (Keppler, 2011; Svoboda, 2011).
2. Opposite cell surface location, complementary function: the apical facil-
itative glucose/galactose transporter on the apical (luminal) surface of
the enterocyte SGLT1 (SLC5A1) is complemented by SLC2A2 (GLUT2)
on the basolateral surface to facilitate the oral absorption of glucose and
other monosaccharides.
3. Complex distributions across multiple tissues and cell locations: entero-
hepatic cycling of bile acids is highly regulated by multiple GIT and
hepatic uptake and efflux transporters (as well as metabolizing enzymes)
(Dawson et al., 2010). Also, transporter-mediated disposition, pharma-
cology and elimination of the glycemic drug metformin are driven by
different transporter isoforms, differentially distributed across multiple
tissues (Nies et al., 2011; Yonezawa & Inui, 2011) (Fig. 2).
Definitive evidence of cellular locations for some transporters in some
tissues is available, but there is no definitive source that describes the loca-
tion of all transporters in all tissues for any species. Some useful public
resources are available, e.g. Human Protein atlas (Knut & Alice Wallenberg
Foundation, 2011), Human ABC transporters (Muller, 2006), and the Bio-
paradigms websites (Heddiger, 2010). Much of this information is drawn
from various other public resources (e.g. PubMed). The content is not
 Membrane Transporters in Drug Development      5

FIGURE 2 Proposed transporter-mediated disposition, pharmacology and elimination of

metformin showing interplay between multiple transporters, differentially distributed across
multiple tissues: In humans, OCT1 is exclusive to hepatocytes and OCT2 to the kidney, whereas
MATEs are present in both organs. OCT1 and OCT2 are virtually absent in other tissues.

always well curated, however, and if not, should be used with some caution,
making reference to relevant expert groups, as necessary.
It appears that there is some redundancy and/or compensatory regulation
of endogenous transporter activity. Most genetically modified animals are via-
ble and fertile, e.g. mdr1a/mdr1b knockout animals are generally healthy
(although highly sensitive to ivermectin exposure compared to wild-type lit-
termates; Lankas et al., 1997). TR-rats which are natural mutants lacking func-
tional mrp2 on the apical surface of hepatocytes, compensate for reduced
biliary elimination of bile acids by expressing higher levels of mrp3 on the baso-
lateral surface resulting in increased bile acids in the blood (Johnson et al.,
2006). Human populations possessing functional mutations of transporters
have also been identified. For example, those with functional SNPs which result
in reduced activity of OATP1B1 have reduced capacity for the statin class of
drugs (Wen & Xiong, 2010), and those with genetic variants in bile salt export
pump (BSEP) have increased susceptibility to cholestasis (Keppler, 2011).
It should also be noted that functional SNPs may result in enhanced
and/or reduced activity of the transporter for its substrates. A recent review
of OATP1B1 clinically relevant SNPs by Niemi et al. (2011) covers the area
well. Although the science is advancing rapidly in many areas, the majority
of transporters have yet to be thoroughly characterized, and their endoge-
nous functions have to be determined. The complexity of the interplay
among multiple transporters, metabolizing enzymes, and other processes is
only beginning to be appreciated, and is a major challenge to industry and
academia in understanding the overall impact on ADME of drugs.
6     J. P. Keogh

C. Transporter Expression Levels

Expression levels of transporters in tissues are usually low as a propor-
tion of the total genomic or proteomic material. Furthermore, in a whole
tissue (e.g. tissue homogenates), it is possible that a transporter may be below
the limits of detection, however, this does not necessarily indicate lack of
functional activity. A recent analysis of protein levels of a number of impor-
tant drug metabolizing enzymes (DMEs) and transporters in human liver
samples from 17 donors gave a range for transporters of 0.06–7.35pmole/
mg protein versus a DME range of 2.4–114pmole/mg protein (Ohtsuki et al.,
2012; Schaefer et al., 2012). As transporter expression is limited to specific
locations on the plasma membrane, it is not unreasonable to expect that
relatively small amounts of transporter protein will be highly effective.
Whilst there are a number of published values for genomic expression
levels of some transporters in some tissues, there is a much smaller body of
work describing their protein expression levels in human tissues and cells.
Furthermore, it appears that there is poor correlation between genomic and
protein expression levels of transporters (Ohtsuki et al., 2012). Recent
advances in absolute immunoquantification methodologies provide an alter-
native to isolated membrane preparation (Tucker et al., 2012). An under-
standing of the functional levels of transporters in vitro versus in vivo is
generally lacking, and needs to be addressed if routine extrapolation of
in vitro data to predict in vivo outcomes has to be successful.

D. Species Differences
There is good information on the transporter gene profiles in rodents
and in humans, however there are many gaps in our knowledge of cross-
species expression and functionality; in particular comparisons of non-
rodent and non-human transporter gene profiles, expression and function
are patchy. From the information available, there seem to be similar trans-
porter complements across species; however there are many instances
where there is no direct homology in expression or function. For instance,
in rodents there are five hepatic oatp transporters (1a1, 1b2, 1a4, 1a5,
and 1a6) compared to three human hepatic OATPs (1B1, 1B3 and 2B1).
There is a single Pgp protein (MDR1) expressed in humans, whereas
rodents express two proteins (mdr1a and mdr1b), which are differentially
distributed across tissues (Shirasaka et al., 2011). In dogs, oatp1b4
appears functionally homologous to OATP1B1 and OATP1B3 (Wilby
et al., 2011). To further complicate cross-species comparison, it appears
that even where transporters are well conserved across species (e.g. OCT1
and OCT2), their relative tissue distribution may not be. In humans,
OCT1 appears to be highly expressed in liver and OCT2 in kidney,
whereas in rodents both homologues are substantially expressed in both
 Membrane Transporters in Drug Development      7

the tissues. OAT transporters show similar differences. Translation of

preclinical findings to predict human outcomes is therefore very challeng-
ing. Digoxin, rosuvastatin and metformin – drugs which are well recog-
nized in vivo substrates of transporters – have markedly different PK and
ADME in rodents versus humans.
Species differences in drug toxicity may also be related to differences in
membrane transporter sub-cellular expression. For instance human
SLC29A1 (ENT1), an equilibrative nucleoside transporter widely expressed
in tissues, has been shown to localize to mitochondrial and plasma mem-
brane in vitro, whereas the murine form localizes only to the plasma mem-
brane (Lee et al., 2006). Thus the enhanced mitochondrial toxicity of
nucleoside drugs such as fialuridine (a known in vitro substrate of ENTs)
observed in humans may be due to species differences in sub-cellular expres-
sion of this transporter.

III. Transporters and the Pharmaceutical Industry 

A. Historical Perspective
Active drug transport in vivo was first observed many decades ago. It
was of particular interest for renally cleared molecules where altered renal
function was associated with disease states (e.g. uric acid clearance and gout;
Gutman & Yu, 1957, 1958). Although the precise mechanisms remained
unknown, in the 1950s scientists and clinicians successfully extended the
elimination half-life of, the then rare drug, penicillin to extend its therapeu-
tic window by co-administration of probenecid (Burnell & Kirby, 1951).
Probenecid was subsequently shown to be a potent inhibitor of members of
the renal organic anion transporters (OATs). During the 1980s drug trans-
porters were identified as mediators of cancer chemo-resistance (refs), in
particular P-glycoprotein (Pgp, MDR1). These discoveries sparked great
interest in the oncology field, and were considered a breakthrough in the
understanding of cancer multiple drug resistance. Although the impact of
efflux transporters such as MDR1 on tumor exposure to drugs was readily
demonstrated in vitro, no successful clinical applications have been licensed
thus far, despite three generations of increasingly potent and selective inhib-
itors (Kelly et al., 2011; Tamaki et al., 2011).
Over the last 10–15 years, the potential and reality of transporter
involvement in the ADME of xenobiotics has become widely accepted
­(Ayrton & Morgan, 2008; Giacomini et al., 2010). After oncology, proba-
bly the earliest appreciation of transporters in drug disposition and efficacy,
and where major effort is still applied in the drug industry, is the delivery of
CNS drugs across the blood–brain barrier (BBB) (Potschka, 2011). Pgp was
identified as a major barrier protein for many CNS drug substances, and to
8     J. P. Keogh

this day, Pgp substrate activity (or lack of it) remains a key selection target
for CNS drug discovery groups.
Since the initial discovery of the Pgp efflux transporter, several other
efflux and uptake transporters involved in chemotherapy drug resistance
have been identified, using experimental and empirical approaches.
The potential for transporters to be mediators of pharmacokinetic (PK)
drug–drug interactions (DDIs) was appreciated relatively soon after the dis-
covery of Pgp, and was adopted as a regulatory requirement for DDI inves-
tigation during the 1990s (Food and Drugs Administration, 2006).
However, the discovery that some HMG-CoA inhibitors (e.g. rosuvastatin,
pravastatin) were substrates of the organic anion transporter protein
(OATP) family, and that inhibition of these transporters could lead to clin-
ically significant PK DDI has arguably been the biggest driver for incorpo-
rating transporter science into mainstream drug development (Shitara &
Sugiyama, 2006). Table I lists transporters which are of current relevance
or interest in the drug development field.
In more recent times, toxicity as a result of modulation of transporter
activity by drugs has been postulated. For example, modulation of multi-
drug resistance protein 2 (MRP2, ABCC2) and the BSEP (ABCB11) by
xenobiotics is now believed to be significant in drug induced liver injury
(DILI) (Dawson et al., 2012). This is not at all surprising, as these transport-
ers (amongst a number of others, as well as certain DMEs) regulate intracel-
lular exposure to toxic bile salts and acids (Dawson et al., 2010).
With the notable exception of CNS drug discovery and delivery, there
has yet to be widespread industry application of transporter science to
improve drug efficacy or delivery in the pharmaceutical industry, although
some companies have successfully exploited transporters for drug delivery
(Xenoport’s Gabapentin pro-drug Enacarbil is the most recent example).
Given the rapid development and acceptance of transportology by the wider
scientific community, appreciation of their potential to impact on drug effi-
cacy in tissues other than the CNS and tumors will continue to increase.

B. Challenges and Opportunities for Drug Development

Clinical safety concerns, notably PK DDI and DILI have proven to be
the greatest drivers for expansion of knowledge and activity for drug trans-
porters in drug development. DDI is more advanced of the two areas, and
will be focused on for the remainder of this chapter.
Drug transporters also offer opportunities to preferentially deliver drugs
to their site of action, or to improve oral bioavailability. But there are sig-
nificant challenges to making these strategies a reality. Nonetheless there
have been successes resulting in improved delivery of some otherwise poorly
bioavailable compounds (e.g. Gabapentin and some antiviral medications).
However, discovery of new CNS drugs has (and still is) severely hampered
TABLE I Listing of Transporters of Current Interest in the Pharmaceutical Industry

Clinically Clinical relevance

Direction of relevant
Tissue transport or Endogeneous Clinically relevant inhibitors Disease
Transporter Gene location orientation substrate(s) substrates (victim) (perpetrator) DDI Toxicity associations
OCT2 SLC22A2 Kidney Blood → cell Creatinine, Metformin, Cimetidine Y Renal tox, N
small organic Varenicline, antivirals
cations Antiretrovirals,
Gabapentin,
Lamotrigine,
Pyrimethamine
OATP1B1 SLCO1B1 Liver Blood → cell Bile salts Statins (e.g. Cyclosporine, Y Hyperbiliru- Rotor

Membrane Transporters in Drug Development     

Rosuvastatin, ­Gemfibrozil, binemia syndrome
OATP1B3 SLCO1B3 Liver Blood → cell Bile salts Pravastatin) Eltrom-
Repaglanide, bopag,
Olmesartan Rifampicin,
Lopinavir/
Ritonavir
BCRP ABCG2 GIT, CNS. Cell → lumen Lipids/cholesterol? Rosuvastatin, GF120918 Y N
liver, Topotecan
kidney,
others
OAT1 SLC22A6 Kidney Blood → cell Organic anions, Methotrexate. Probenecid Y Renal N
polyspecific, e.g. Antiretrovirals
α-ketoglutarate (e.g. Zidovu-
dine, Acyclovir),
NSAIDs
OAT3 SLC22A8 Kidney Blood → cell Organic anions, Methotrexate Probenecid Y Renal N
polyspecific
(continued)

9
TABLE I Listing of Transporters of Current Interest in the Pharmaceutical Industry (continued)

10    
Clinically Clinical relevance
Direction of relevant
Tissue transport or Endogeneous Clinically relevant inhibitors Disease

J. P. Keogh
Transporter Gene location orientation substrate(s) substrates (victim) (perpetrator) DDI Toxicity associations
Ppg/MDR1 ABCB1 GIT, CNS. Cell → lumen Lipids/cholesterol? Digoxin Quinidine, Y N
liver, Ritonavir
kidney,
others
OCT1 SLC22A1 Liver Blood → cell Organic cations, Metformin, Not demon- Y N
polyspecific Antiretroviral strated
drugs
BSEP ABCB11 Liver Cell → bile Bile salts unproven Lapatinib N DILI Unk
NTCP SLC10A1 Liver Blood → cell Na-taurocholate, Not demonstrated Bosentan N DILI Unk
bile salts
MATE1 SLC47A1 Kidney, Cell → lumen Organic cations Metformin Cimetidine? Suspected N
liver
MATE2 SLC47A2 Kidney, Cell → lumen Organic cations Metformin Cimetidine? Suspected N
testis,
colon
OAT4 SLC22A11 Kidney Cell → urine Organic anions, Methotrexate Probenecid Y N
polyspecific, e.g.
urate
OAT2 SLC22A7 Liver Blood → cell Organic anions, Not demonstrated Not demon- N N
polyspecific, e.g. strated
cGMP
OCT3 SLC22A3 Ubiquitous Blood → cell Organic cations, Not demonstrated Not demon- N N
polyspecific strated
OCTN1 SLC22A4 Ubiquitous Blood → cell Ergothionine Not demonstrated Not demon- N Unk
strated
(continued)
TABLE I Listing of Transporters of Current Interest in the Pharmaceutical Industry (continued)

Clinically Clinical relevance

Direction of relevant
Tissue transport or Endogeneous Clinically relevant inhibitors Disease
Transporter Gene location orientation substrate(s) substrates (victim) (perpetrator) DDI Toxicity associations
OCTN2 SLC22A5 Heart, Blood → cell Carnitine Not demonstrated Not demon- N Carnitine Y
lung, strated deficiency
wide-
spread
PEPT1 SLC15A1 GIT Gut → cell Di/tri-peptides B-Lactam Not demon- N N
antibiotics. strated
Valacyclovir

Membrane Transporters in Drug Development     

MCT1 SLC16A1 Ubiquitous Lumen → cell Lacate, pyruvate, Gabapentin-Enar- Not demon- N Unk
ketone bodies cabil strated
MRP2 ABCC2 GIT, liver, Cell → lumen Bilirubin glucs, Not demonstrated Not demon- Suspected DILI Dubin-
kidney, strated Johnson
others Syndrome
MRP3 ABCC3 GIT, liver, Cell → blood Glutathione Ethynyl estradiol Not demon- Suspected Cholestasis, Unk
kidney (liver) conjugates, bile metabolites strated DILI
salts
MRP4 ABCC4 Many Cell → blood Cyclic nucleotides, Not demonstrated Not demon- N Cholestasis, Unk
tissues (liver) bile salts strated DILI
GLUTs SLC2 family Wide- Cell → blood Glucose and other Not demonstrated Not demon- N Type 2
spread sugars strated diabetes
SGLTs SLC5 family Wide- Lumen → cell Glucose and other Not demonstrated Not demon- N Type 2
spread sugars strated diabetes
ASBT SLC10A2 GIT Gut → cell Bile salts Not demonstrated Not demon- N Unk
strated
(continued)

11
TABLE I Listing of Transporters of Current Interest in the Pharmaceutical Industry (continued)

12    
Clinically Clinical relevance
Direction of relevant
Tissue transport or Endogeneous Clinically relevant inhibitors Disease

J. P. Keogh
Transporter Gene location orientation substrate(s) substrates (victim) (perpetrator) DDI Toxicity associations
OSTα/β SLC51A1 GIT Cell → blood Bile acids Not demonstrated Not demon- N Unk
and A1BP strated
OATP1A2 SLCO1A2 Brain, Blood → cell Bile salts Not demonstrated Not demon- Suspected Unk
kidney, strated
liver
OATB2B1 SLCO2B1 Liver, Blood → cell Not demonstrated Not demon- Suspected Unk
intestine strated

Bolded entries are implicated in DDI for important drug classes, and regulatory authorities recommend the NCE be assessed for DDI liability against these.
Others are of lesser DDI importance and/or are implicated in drug delivery or drug toxicity. Some transporters may have wider tissue distribution than
indicated. Where multiple tissue expression is listed, “Lumen” has generally been used to indicate that substrates may be transported from/to different
compartments (e.g. blood, bile or urine).