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8/17/2019 1. Transporter-Mediated Disposition of Opioids Implications for Clinical Drug Interactions
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EXPERT REVIEW
Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions
Robert Gharavi1,2 & William Hedrich1 & Hongbing Wang1 & Hazem E. Hassan1,3
Received: 30 March 2015 /Accepted: 6 May 2015# Springer Science+Business Media New York 2015
ABSTRACT Opioid-related deaths, abuse, and drug inter-
actions are growing epidemic problems that have medical,
social, and economic implications. Drug transporters play a
major role in the disposition of many drugs, including opioids;hence they can modulate their pharmacokinetics, pharmaco-
dynamics and their associated drug-drug interactions (DDIs).
Our understanding of the interaction of transporters with
many therapeutic agents is improving; however, investigating
such interactions with opioids is progressing relatively slowly
despite the alarming number of opioids-mediated DDIs that
may be related to transporters. This review presents a
comprehensive report of the current literature relating
to opioids and their drug transporter interactions.
Additionally, it highlights the emergence of transporters
that are yet to be fully identified but may play promi-
nent roles in the disposition of opioids, the growing
interest in transporter genomics for opioids, and the
potential implications of opioid-drug transporter interac-
tions for cancer treatments. A better understanding of
drug transporters interactions with opioids will provide great-
er insight into potential clinical DDIs and could help improve
opioids safety and efficacy.
KEY WORDS opioid abuse . opioid DDI . opioid drug transporters . opioids and P-gp
ABBREVIATIONS6-MAM 6-monoacetylmorphine
AAPCC American Association for Poison Control Centers
AUC Area under the curveBBB Blood – brain barrier
BCRP Breast cancer resistance protein
CLin Permeability clearance into the brain
CNS Central nervous system
DDI Drug-drug interaction
ED Emergency department
FDA Food and Drug Administration
GLUT Glucose transporters
HEK293 Human embryonic kidney 293
IC50 Half maximal inhibitory concentration
K i Inhibition constant
K p,uu Ratio of unbound drug in the brain to unbound
drug in the blood
M3G Morphine-3-glucuronide
M6G Morphine-6-glucuronide
MDMA 3,4-methylenedioxy-methamphetamine
MMT Methadone maintenance treatment
MOR μ-opioid receptor
MRP Multidrug resistance-associated proteins
NSDUH National Survey on Drug Use and Health
OAT Organic anion transporters
OATP Organic anion-transporting polypeptides
OCT Organic cation transporters
PD Pharmacodynamics
P-gp P-glycoprotein
PK Pharmacokinetics
V u,brain Volume of distribution within the brain
INTRODUCTION
Opioids are the standard analgesics of choice for the treat-
ment of chronic and severe pain, as well as cancer-pain
* Hazem E. [email protected]
1 Department of Pharmaceutical Sciences, University of Maryland Schoolof Pharmacy, 20 N Pine Street, Rooms: N525 (Office)Baltimore, Maryland 21201, USA
2 Clinical Development, MedImmune, One MedImmune Way Gaithersburg, Maryland 20878, USA
3 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo, Egypt
Pharm Res
DOI 10.1007/s11095-015-1711-5
8/17/2019 1. Transporter-Mediated Disposition of Opioids Implications for Clinical Drug Interactions
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management ( 1, 2 ). In addition to their clinical applications in
pain management, opioids have a long history of illicit abuse.
Opioids comprise a large family of both naturally occurring
and synthetic molecules that are classified by their interactions
with the three opioid receptors: μ, δ, and κ ( 3 ). μ-opioid re-
ceptor (MOR) agonists are known to produce the euphoric
and analgesic effects most commonly associated with physical
dependence and abuse ( 4 ).The United States (US) is presently facing a severe epidem-
ic of drug overdose deaths which appears to be driven primar-
ily by opioid abuse ( 5 – 8 ). The number of deaths related to
opioid overdose has more than quadrupled since 1999, direct-
ly correlating with the dramatic increase in the sale of opioid
pharmaceuticals ( 7, 9, 10 ). In 2010 an estimated 46 Americans
were dying each day from opioid overdoses while 210 million
opioid prescriptions were dispensed by U.S. retail pharmacies
( 10, 11 ). Further, in 2011 alone over 190,000 emergency de-
partment visits were believed to be due to adverse events
resulting from narcotic pain relieving medications, and 400,
000 emergency department visits were related to opioid anal-gesic abuse ( 12 ). Hence, greater measures are urgently needed
to increase the drug safety of opioids, including greater under-
standing of their pharmacokinetic mechanisms and potential
drug-drug interactions (DDIs).
Although not as well recognized as metabolizing enzymes,
membrane drug transporters are being increasingly acknowl-
edged as important determinants of drug pharmacokinetics
(PK), pharmacodynamics (PD) and DDIs ( 13 ). Regulatory
agencies from the US, European Union and Japan have all
released guidances in recent years addressing the emerging
clinical significance of drug transported-mediated DDIs
( 14 – 17 ). The 2012 US Food and Drug Administration
(FDA) Guidance for Industry on drug interaction studies
outlined 7 transporters with which a developing drug should
be evaluated for interactions with. These transporters of inter-
est are P-glycoprotein (P-gp/MDR1, ABCB1), Breast Cancer
Resistance Protein (BCRP, ABCG2), the hepatic uptake
Organic Anion Transporting Polypeptides (OATP) 1B1 and
1B3, and the renal Organic Anion Transporter (OAT) 1 and
3, and Organic Cation Transporter 2 (OCT2) ( 16 ). In addi-
tion, there are multiple emerging transporters of interest, such
as members of the multidrug and toxic compound extrusion
(MATE) family, as well as a number of yet to be fully identified
transporters ( 18 – 20 )(Fig. 1 ).
The antidiarrheal loperamide is a prime example of the
impact drug transporters may have on the PK/PD of opioids.
Loperamide exhibits minimal central nervous system (CNS)
activity due to being a substrate of P-gp, an efflux transporter
with broad substrate specificity, at the blood – brain barrier
(BBB) ( 21 ). Clinically significant transporter-mediated DDIs
have already been demonstrated for a number of commonly
used medications including multiple statins, cimetidine, digox-
in, metformin, anti-epileptics and anti-cancer agents, to name
a few ( 16 ). Thus, the role of drug transporters in drug PK/PD,
toxicity, human disease, and inter-individual variability in
drug response is an emerging field of interest, however their
contributions to the disposition of opioids in humans remains
largely unexplored ( 17 ).
In order to most accurately predict their potential clinical
implications, it is essential to have mechanisms in place that
can quantitatively evaluate transporter-mediated DDIs. Forexample, transporter-mediated DDIs that occur in preclinical
studies may not be applicable to the clinic due to the unsafe or
non-clinically relevant doses at which they occur. Since opi-
oids are primarily used for their centrally acting analgesic
effects, their drug transporter interactions at the BBB are of
particular interest. Previous studies have proposed that the
rate and extent of drug delivery to the brain in vivo can be
comprehensively described by three parameters: the ratio of
concentration of unbound drug in the brain to the unbound
concentration in the blood (K p,uu ), the permeability clearance
into the brain (CLin ), and the volume of distribution within the
brain (V u,brain ) ( 22 ).The purpose of this review article is to highlight the influ-
ence of drug transporters on the disposition of opioids to pre-
dict clinical implications and to improve both their safety and
efficacy. When applicable, we provide for each opioid a sys-
tematic review of in vitro, in vivo (animal) and clinical data
regarding drug-transporter interactions, and highlight the po-
tential clinical implications of these interactions that warrant
further investigation.
OPIOIDS OF ABUSE
Morphine
Morphine is considered the prototypical opioid and gold stan-
dard to which other strong analgesics are compared ( 23 ). The
major metabolite of morphine is morphine-3-glucuronide
(M3G), which has no analgesic properties but elicits neuro-
excitatory effects. Approximately 10% of morphine is metab-
olized to morphine-6-glucuronide (M6G) which has much
greater analgesic effects than its parent compound. Both
M3G and M6G are products of morphine metabolism by
UGT2B7 in the liver ( 24 ). Although markedly more potent
than morphine at the μ-opioid receptor, M6G exhibits poor
blood – brain BBB permeability ( 25 ). Morphine itself exhibits a
lower CLin than most opioids, though it is at least 10-fold
higher than M6G. Similarly, morphine’s K p,uu and V u,brainappears to be many folds higher than M6G’s ( 26 – 28 ). An
estimated 4 million morphine containing prescriptions were
dispensed in 2009 ( 29 ). In 2011 nearly 35,000 emergency
department (ED) visits were reportedly due to abuse of
morphine products, representing an over 100% increase
from 2004 ( 12 ).
Gharavi, Hedrich, Wang and Hassan
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A number of in vitro studies have demonstrated that mor-
phine ( 30 – 34 ) and M6G ( 35 ) are likely P-gp substrates.
Conversely, Tournier et al., suggested morphine is neither a
P-gp nor BCRP substrate ( 36 ), and Wandel et al., suggested
that neither M3G nor M6G are P-gp substrates ( 33 ). Both
Morphine and codeine were shown to inhibit OCT1 mediat-
ed uptake at 100 μM in HEK293 cells overexpressing OCT1
( 37 ), while morphine, but not codeine, was shown to be anOCT1 substrate in this same model cell line as well as in
primary hepatocytes. Further, a number of medications that
are cationic at physiological pH were shown to inhibit mor-
phine’s OCT1 mediated uptake in a concentration-
dependent manner at clinically relevant doses, such as
irinotecan (IC50=1.5 μM), ondansetron (IC50=1.17 μM),
and verapamil (IC50=1.6 μM) ( 38 ). In vitro studies have also
suggested that M6G and M3G are both multidrug resistance-
associated protein 2 (MRP2) and MRP3 substrates in hepato-
cytes ( 39, 40 ).
Although there is evidence of an active influx at the BBB
( 41, 42 ), it appears that morphine largely undergoes a netefflux at the BBB in vivo ( 41, 43 – 45 ). A number of animal
studies have demonstrated morphine to be a likely P-gp sub-
strate. P-gp inhibitors were shown to increase CNS concen-
trations and antinocipetive effects of morphine ( 46 – 49 ).
Similarly, P-gp knock-out mice administered morphine had
significantly increased analgesia ( 50, 51 ) and brain distribution
( 30, 41, 52 ). A negative correlation was also found between P-
gp expression levels in the brains of rats and morphine-
induced analgesia ( 53 ). Correspondingly, P-gp was found to
be up-regulated in the brains of morphine tolerant rats ( 47 )
and the down-regulation of rat Pgp1 with antisense prevented
morphine tolerance development and reduced morphine’s
brain-to-blood efflux ( 54 ). Morphine was also shown to signif-
icantly inhibit the proton-coupled antiporter transport of
clonidine at the BBB of mice (20 reduction in clonidine
brain transport at a concentration of 10 mM). However,
this does not represent a clinically relevant concentration of
morphine and the authors have suggested that morphine
is unlikely to be an efficient substrate of this emerging
transporter ( 19 ).
Rats administered M6G intravenously along with a known
P-gp inhibitor were found to have significantly increased
M6G antinociception and a 3-fold increase in CNS M6G
relative to those not administered the inhibitor ( 55 ).
However, Bourasset et al., demonstrated M6G to be neither
a P-gp nor Mrp1 substrate, but rather a GLUT1 and/or
possibly a weak Oatp2-like substrate at the BBB in mice
( 56 ). Other knockout mice studies have suggested that Mrp2
and Mrp3 play important roles in the hepatic excretion of
M3G and M6G and modulate the antinociception of M6G
( 39, 40 ). Another study indicated that probenecid significantly
decreased the systemic elimination by 22% but had no effect
on the BBB transport of M6G in rats, suggesting M6G may be
a substrate of a probenecid-sensitive transporter (OAT) out-
side the CNS ( 57 ).
A number of clinical studies have supported the hypothesis
that morphine and its glucuronide metabolites are P-gp sub-
strates. One case report noted that concomitant administra-
tion of known P-gp inducer rifampin with morphine resulted
in noticeably decreased morphine blood levels ( 58 ). Patients
deemed to have P-gp positive tumors from immunohisto-chemistry (IHC) results were found to require higher doses
of morphine for pain control, relative to those with P-gp neg-
ative tumors ( 59 ). However, another study investigating the
CNS effects of morphine coadministered with a known P-gp
inhibitor found no clinically significant differences relative to
controls. The plasma pharmacokinetics of morphine and
M6G were unaffected by P-gp inhibition, while the area un-
der the curve (AUC) and half-life (t1/2 ) of M3G were signifi-
cantly increased ( 60 ). Concomitant use of known P-gp inhib-
itor cyclosporine with morphine in healthy volunteers resulted
in significantly increased morphineAUC relative to controls,
though the authors proposed this may not have any majorclinical effects ( 61 ).
ABCB1, the gene that encodes P-gp, has been reported to
have certain polymorphisms which may predispose patients to
morphine-induced adverse events ( 62 ) and variable pain relief
( 63 ). However, Coulbault et al., demonstrated that ABCB1
polymorphisms appeared to have no association with mor-
phine doses post-operatively, and only borderline association
( p=0.07) with morphine-induced side effects ( 64 ). In line with
the group’s in vitro findings, Tzvetkov et al., demonstrated that
following oral administration of codeine, the AUC of mor-
phine, but not codeine, was greatly affected by OCT1 poly-
morphisms. Patients homozygous for OCT1 loss-of-function
polymorphisms were found to have 1.5 fold higher
morphineAUC relative to those heterozygous and homozygous
for functional OCT1 alleles ( 38 ). Similarly, a clinical study of
children undergoing adenotonsillectomy found that subjects
homozygous for OCT1 loss-of-function variants had signifi-
cantly lower (20%) morphine clearances than wild-types or
those heterozygous for such variants ( 65 ).
Despite numerous studies there currently appears to be no
definitive consensus regarding the role of P-gp in the disposi-
tion of morphine or its glucuronidated metabolites. Preclinical
evidence mostly suggests morphine is a P-gp substrate, while
clinical data appears inconsistent. One transporter of increas-
ing interest in morphine’s disposition, particularly its hepatic
efflux, is OCT1. In vitro and clinical data are in agreement that
OCT1 plays an important role in the pharmacokinetics of
morphine. These findings may imply a host of potential
transporter-based clinical DDIs with other OCT1 substrates
or inhibitors (Table I ), some of which have already been dem-
onstrated in vitro at clinically relevant concentrations ( 38 ).
OCT1-mediated DDIs between morphine and other
substrates/inhibitors could lead to impaired hepatic clearance
Drug Transporter Interactions with Opioids
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T a b l e I
S u m m a r y o f O p i o i d - D r u g T
r a n s p o r t e r I n t e r a c t i o n s a n d T h e i r P o t e n t i a l I m p l i c a t i o n s
D r u g N a m e
T r a n s p o r t e r
E v i d e n c e
C l i n i c a l i m p l i c a t i o n s
M o r p h i n e
P - g p
I n v i t r o :
M o r p h i n e i s
a s u b s t r a t e ( 3 0 –
3 4 )
M o r p h i n e i s
n o t a s u b s t r a t e ( 3 6 )
M 6 G i s a s u b s t r a t e ( 3 5 )
M 3 G a n d M
6 G a r e n o t a s u b s t r a t e s ( 3 3 )
I n v i v o :
M o r p h i n e i s
a s u b s t r a t e ( 3 0 ,
4 1 ,
4 6 – 5 4 )
M 6 G i s a s u b s t r a t e ( 5 5 )
M 6 G i s n o t a s u b s t r a t e ( 5 6 )
C l i n i c a l :
M o r p h i n e i s
a s u b s t r a t e ( 5 8 ,
5 9 ,
6 1 )
M o r p h i n e a n
d M 6 G a r e n o t s u b s t r a t e s , w h i l e M 3 G i s
a p o s s i b l e
s u b s t r a t e ( 6 0 )
A B C B 1 p o l y
m o r p h i s m s i m p a c t m o r p h i n e P K / P D ( 6 2 ,
6 3 )
A B C B 1 p o l y
m o r p h i s m s h a v e n o i m p a c t o n m o r p h i n e P K / P D
( 6 4 )
T h e r o l e o f P - g p i n t h e d i s p o s i t i o n o f m o r p h i n e a n d
i t s g l u c u r o n i d a t e d m e t a b o l i t e
s i s u n c l e a r .
B C R P
I n v i t r o :
M o r p h i n e i s
n o t a s u b s t r a t e ( 3 6 )
L i m i t e d e v i d e n c e s u g g e s t s m o r p h i n e m a y
n o t b e a B C R P s u b s t r a t e
O C T 1
I n v i t r o :
M o r p h i n e i s
a n i n h i b i t o r ( 3 7 )
M o r p h i n e i s
a s u b s t r a t e ( 3 8 )
C l i n i c a l :
O C T 1 p o l y m o r p h i s m s i m p a c t P K o f m o r p h i n e ( 3 8 ,
6 5 )
M o r p h i n e a p p e a r s t o b e a l i k e l y O C T 1
s u b s t r a t e / i n h i b i t o r , i n f e r r i n g p
o t e n t i a l c l i n i c a l
D D I s w i t h o t h e r O C T 1 s u b s t r a t e s w h i c h
m a y i n c l u d e a c y c l o v i r ( 6 6 ) , m
e t f o r m i n ( 6 7 – 7 2 ) ,
i m a t i n i b ( 7 3 ) , o x a l i p l a t i n ( 7 4 ) , r a n i t i d i n e ,
( 7 5 )
a n d i n h i b i t o r s s u c h a s q u i n i d i n e ( 7 5 ) , a t r o p i n e ,
d i p h e n h y d r a m i n e ( 7 6 ) , a m i t r i p t y l i n e ( 6 8 ) ,
m e m a n t i n e , c o c a i n e ( 7 7 ) , p r
a z o s i n ( 7 8 ) ,
r o s i g l i t a z o n e ( 7 9 ) , p i o g l i t a z o n
e ( 6 8 ) ,
v e r a p a m i l ( 7 8 ) , t r a m a d o l ( 8 0
) , a n d a t c l i n i c a l l y
r e l e v a n t d o s e s o f i r i n o t e c a n ( I C 5 0 = 1 . 5
μ M )
a n d o n d a n s e t r o n ( I C 5 0 = 1 . 1
7 μ M ) ( 3 8 ) .
I m p a i r e d h e p a t i c c l e a r a n c e o f m
o r p h i n e c o u l d
l e a d t o l o n g e r m o r p h i n e e x p
o s u r e s i n p a t i e n t s
a n d i n c r e a s e t h e i r r i s k s o f a d v e r s e e v e n t s s u c h a s
r e s p i r a t o r y d e p r e s s i o n , s e v e r e h y p o t e n s i o n ,
m y o c l o n i c s p a s m s , c o n s t i p a t i o n , a n d o t h e r s ( 2 9 ) .
O C T 3
I n v i t r o :
M o r p h i n e i s
n o t a s u b s t r a t e ( 3 8 )
L i m i t e d e v i d e n c e s u g g e s t s m o r p h i n e
i s n o t a n O C T 3 s u b s t r a t e .
G L U T - 1
I n v i v o :
M 6 G i s a s u b s t r a t e a t t h e B B B ( 5 6 ,
8 1 )
H e r o i n a n d m o r p h i n e m a y a f f e c t g l u c o s e
t r a n s p o r t a t t h e B B B
M R P 1
I n v i v o :
M 6 G i s n o t a s u b s t r a t e ( 5 6 )
M R P 2 a n d M R P 3 a p p e a r t o b e
i n v o l v e d i n h e p a t i c
e x c r e t i o n o f m o r p h i n e g l u c u r o n i d a t e d m e t a b o l i t e s .
T h i s c o u l d i n f e r t r a n s p o r t e r - b a s e d D D I s w i t h o t h e r
M R P 2 a n d M R P 3 s u b s t r a t e s
a n d i n h i b i t o r s .
P o s s i b l e M R P 2 s u b s t r a t e s i n c l u d
e o l m e s a r t a n ( 8 2 ) ,
v a l s a r t a n ( 8 3 ) , e t o p o s i d e ( 8 4
) , i r i n o t e c a n ( 8 5 ) ,
M R P 2
I n v i t r o & i n v i v o :
M 3 G i s a s u b s t r a t e ( 3 9 ,
4 0 )
M R P 3
I n v i t r o :
Gharavi, Hedrich, Wang and Hassan
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T a b l e I
( c o n t i n u e d )
D r u g N a m e
T r a n s p o r t e r
E v i d e n c e
C l i n i c a l i m p l i c a t i o n s
m e t h o t r e x a t e ( 8 6 ) , v i n b l a s t i n
e ( 8 7 ) , a n d i n h i b i t o r s
i n c l u d e c y c l o s p o r i n e A ,
d a u n
o r u b i c i n , e t o p o s i d e ,
v i n c r i s t i n e ( 8 7 ) , e f a v i r e n z , e m
t r i c i t a b i n e ,
d e l a v i r d i n e
( 8 8 ) , i n d o m e t h a c i n ,
k e t o p r o f e n ( 8 6 ) .
P o s s i b l e M R P 3 s u b s t r a t e s i n c l u d
e f e x o f e n a d i n e ( 8 9 ) ,
m e t h o t r e x a t e ,
f o l i c a c i d ,
l e u c
o v o r i n ( 9 0 ) , a n d
i n h i b i t o r s e f a v i r e n z , e m t r i c i t a
b i n e , a n d
d e l a v i r d i n e ( 8 8 )
M 6 G i s a s u b s t r a t e ( 3 9 ,
4 0 )
I n v i v o :
M 3 G i s a s u b s t r a t e ( 3 9 ,
4 0 )
D i g o x i n - s e n s i t i v e t r a n s p o r t e r
I n v i v o :
M 6 G i s a w e a k s u b s t r a t e a t t h e B B B ( 5 6 )
T h e i d e n t i t y o f t h i s t r a n s p o r t e r h a s n o t y e t b e e n
e s t a b l i s h e d ,
b u t m a y b e O A T
P 1 B 1 .
T h i s c o u l d
i m p l y p o t e n t i a l D D I s w i t h O
A T P 1 B 1 s u b s t r a t e s
s u c h a s p i t a v a s t a t i n , r o s u v a s t a t i n ( 9 1 ) , s i m v a s t a t i n
( 9 2 ) , d o c e t a x e l ( 9 3 ) , p a c l i t a x e l ( 9 4 ) , f e x o f e n a d i n e
( 9 5 ) , g l y b u r i d e ( 9 6 ) , a n d d i g o x i n ( 9 7 ) , a s w e l l
a s l i k e l y O A T P 1 B 1 i n h i b i t o r s
s u c h a s r i t o n a v i r
( 9 7 ,
9 8 ) , a t a z a n a v i r , d a r u n a v i r , i n d i n a v i r , l o p i n a v i r
( 9 8 ) , a n d v e r a p a m i l ( 9 2 )
P r o b e n e c i d - s e n s i t i v e t r a n s p o r t e r ( O A T )
I n v i v o :
M 6 G i s a p o
s s i b l e s u b s t r a t e o u t s i d e t h e B B B ( 5 7 )
T h e i d e n t i t y o f t h i s t r a n s p o r t e r h a s n o t y e t b e e n
e s t a b l i s h e d .
I f M 6 G i s a n O A T s u b s t r a t e , t h e
r e m a y b e p o t e n t i a l
D D I s b e t w e e n m o r p h i n e a n
d o t h e r O A T P
s u b s t r a t e s s u c h a s
a c y c l o v i r ( 9 9 ) , c i d o f o v i r ( 1 0 0 ) , a n u m b e r o f
c e p h a l o s p o r i n s s u c h a s c e f a c l o r ( 1 0 1 ) , c e f o n i c i d
( 1 0 2 ) , c e f t r i a x o n e ( 1 0 3 ) , a n d
c e p h r a d i n e ( 1 0 1 ) ,
c i p r o f l o x a c i n ( 1 0 4 ) , d i c l o x a c i l l i n ( 1 0 5 ) , f a m o t i d i n e
( 1 0 6 ) , a n d f u r o s e m i d e ( 1 0 7 )
, a s w e l l a s w i t h
O A T i n h i b i t o r s s u c h a s p r o b e n e c i d ( 1 0 5 ) a n d
s u l f a m e t h o x a z o l e - t r i m e t h o p r i m ( 1 0 8 ) .
P r o t o n - c o u p
l e d a n t i p o r t e r
I n v i v o :
P o s s i b l e w e a
k i n h i b i t o r / s u b s t r a t e o f t h e p r o t o n - c o u p l e d
a n t i p o r t e r
o f c l o n i d i n e a t t h e B B B ( 1 9 )
M o r p h i n e w a s f o u n d t o s i g n i f i c a n t l y r e d u c e t h e b r a i n
t r a n s p o r t o f c l o n i d i n e b y 2 0 %
a t a c o n c e n t r a t i o n
o f 2 0 m M .
T h i s d o e s n o t r e p r e s e n t a c l i n i c a l l y
r e l e v a n t c o n c e n t r a t i o n a n d s o c l i n i c a l D D I s m a y
b e u n l i k e l y .
F u r t h e r s t u d i e s a r e w a r r a n t e d .
C o d e i n e
O C T 1
I n v i t r o :
I n h i b i t o r ( 3 7 )
N o t a s u b s t r
a t e ( 3 8 )
R o l e o f O C T 1 i s n o t c l e a r
P r o t o n - c o u p
l e d a n t i p o r t e r
I n v i t r o :
P o s s i b l e s u b s t r a t e a t i n t e s t i n a l e p i t h e l i u m a n d B B B ( 1 0 9 )
P o s s i b l e s u b s t r a t e o f t h i s y e t t o
b e f u l l y i d e n t i f i e d t r a n s p o r t e r . .
T h e c e l l u l a r u p t a k e o f c o d e i n e ( 1 . 2 n M ) w a s p o t e n t l y
i n h i b i t e d i n t h e p r e s e n c e o f p y r i l a m i n e , c l o n i d i n e ,
d i p h e n h y d r a m i n e , p r o p r a n o l o l , v e r a p a m i l , a s w e l l
a s a n u m b e r s o f d r u g s o f a b u s e ,
i n c l u d i n g D - a n d
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T a b l e I
( c o n t i n u e d )
D r u g N a m e
T r a n s p o r t e r
E v i d e n c e
C l i n i c a l i m p l i c a t i o n s
L - a m p h e t a m i n e , c o c a i n e , a n
d m e t h a m p h e t a m i n e
( a l l a t 2 m M ) ( 1 0 9 ) .
M o r e s t u d i e s a r e n e c e s s a r y t o d e t e r m i n e i f t h e s e
D D I s o c c u r a t c l i n i c a l l y r e l e v a n t c o n c e n t r a t i o n s .
D i a c e t y l m o r p h i n e
P - g p
I n v i v o :
N o t a s u b s t r
a t e ( 4 9 )
D i a c e t y l m o r p h i n e a n d 6 - M
A M
d o n o t a p p e a r
t o b e P - g p s u b s t r a t e s
P r o t o n - c o u p
l e d a n t i p o r t e r
I n v i v o :
P o s s i b l e i n h i b i t o r o f t h e p r o t o n - c o u p l e d a n t i p o r t e r
o f c l o n i d i n
e a t t h e B B B ( 1 9 )
P o s s i b l e i n h i b i t o r o f t h i s y e t t o b e f u l l y i d e n t i f i e d
t r a n s p o r t e r a t t h e B B B .
C o u l d b e a s o u r c e o f a n u m b e r o f c l i n i c a l D D I s b e t w e e n
d i a c e t y l m o r p h i n e a n d o t h e r p o t e n t i a l s u b s t r a t e s /
i n h i b i t o r s i n c l u d i n g c l o n i d i n e ,
d i p h e n h y d r a m i n e ,
t r a m a d o l a n d n i c o t i n e , c o d e i n e , m o r p h i n e , c o c a i n e ,
a n d M D M A ( 1 9 ,
2 0 )
O x y c o d o n e
P - g p
I n v i t r o :
S u b s t r a t e ( 1 1 0 )
I n v i v o :
S u b s t r a t e ( 1 1 0 ,
1 1 1 )
N o t a s u b s t r
a t e ( 1 1 2 )
C l i n i c a l :
C 3 4 3 5 T a n d
G 2 6 7 7 T / A A B C B 1 p o l y m o r p h i s m s l i n k e d t o l e
s s
a d v e r s e e
f f e c t s o f o x y c o d o n e ( 1 1 3 )
M o t h e r s w i t h a t l e a s t o n e 2 6 7 7 T c o p y h a d i n c r e a s e d r i s k o f
o x y c o d o n
e - i n d u c e d s e d a t i o n ( 1 1 4 )
C 3 4 3 5 T p o l y m o r p h i s m h a d n o e f f e c t s o n o x y c o d o n e P K ( 1
1 5 )
R o l e o f P - g p i s h i g h l y c o n t r o v e r
s i a l ( 1 1 6 )
B C R P
I n v i v o :
I n d u c e r ( 1 1 7
)
C o n c o m i t a n t u s e o f o x y c o d o n e
w i t h o t h e r B C R P
s u b s t r a t e s c o u l d r e s u l t i n t r a n s p o r t e r - m e d i a t e d D D I s ,
w h i c h m a y i n c l u d e d a u n o r u b
i c i n ,
d o x o r u b i c i n ,
m e t h o t r e x a t e ,
i m a t i n i b ,
l a p a t a n i b ,
i r i n o t e c a n , a n d
t o p o t e c a n ( 1 6 ) , a s w e l l a s n o
n - c h e m o t h e r a p y a g e n t s
s u c h a s n i t r o f u r a n t o i n , p r a z o s i n , g l y b u r i d e ( 1 1 8 ) ,
r o s u v a s t a t i n , s u l f a s a l a z i n e ( 1 6
) , a n d f e l l o w d r u g o f
a b u s e , m a r i j u a n a ( 3 6 ,
1 1 9 , 1
2 0 )
P r o t o n - c o u p
l e d a n t i p o r t e r
I n v i t r o & i n v i v o :
S u b s t r a t e o f
t h e p r o t o n - c o u p l e d a n t i p o r t e r o f p y r i l a m i n e
a t t h e B B B ( 1 2 1 ,
1 2 2 )
P o s s i b l e s u b s t r a t e o f t h i s y e t t o
b e f u l l y i d e n t i f i e d
t r a n s p o r t e r a t t h e B B B .
I n
v i t r o
r e s u l t s s u g g e s t s i g n i f i c a n t l y
i n h i b i t e d B B B u p t a k e o f o x y c
o d o n e ( 3 0 μ M ) i n t h e
p r e s e n c e o f p y r i l a m i n e ( 1 m M ) , q u i n i d i n e ( 1 m M ) ,
v e r a p a m i l ( 1 m M ) , a m a n t a d i n e ( 1 m M ) ( 1 2 1 ) ,
a m i t r i p t y l i n e ( K i = 1 3 μ M ) , f l u v o x a m i n e ( K i =
6 5 μ M ) ,
a n d m e x i l e t i n e ( K i = 4 4 μ M )
( 1 2 2 )
H o w e v e r , t h e s e D D I s o c c u r r e d a t v e r y h i g h
c o n c e n t r a t i o n s a n d m a y n o t
b e c l i n i c a l l y r e l e v a n t .
F u r t h e r i n v e s t i g a t i o n s a r e w a
r r a n t e d .
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T a b l e I
( c o n t i n u e d )
D r u g N a m e
T r a n s p o r t e r
E v i d e n c e
C l i n i c a l i m p l i c a t i o n s
I n v i t r o :
S u b s t r a t e o f
t h e p r o t o n - c o u p l e d a n t i p o r t e r o f d i p h e n h y d r a m
i n e
a t t h e B B B ( 1 2 3 ,
1 2 4 )
I n
v i t r o
r e s u l t s s u g g e s t o x y c o d o n e a n d d i p h e n h y d r a m i n e
s h a r e t h i s y e t t o b e f u l l i d e n t i f i e d a c t i v e t r a n s p o r t e r a t
t h e B B B .
H o w e v e r , i n
v i v o r e
s u l t s s u g g e s t o x y c o d o n e
a n d d i p h e n h y d r a m i n e d o n o
t h a v e a s i g n i f i c a n t D D I
a t t h e B B B a t n o n - t o x i c c o n c
e n t r a t i o n s , m a k i n g a
c l i n i c a l D D I u n l i k e l y a t t h e r a p
e u t i c d o s e s ( 1 2 3 )
O x y m o r p h o n e
P - g p
I n v i t r o :
N o t a s u b s t r
a t e ( 1 1 1 )
L i m i t e d e v i d e n c e s u g g e s t s o x y m
o r p h o n e i s n o t a
l i k e l y P - g p s u b s t r a t e
U n i d e n t i f i e d
B B B t r a n s p o r t e r
I n v i v o :
O x y m o r p h o
n e u n d e r g o e s a c t i v e t r a n s p o r t a t B B B b y a
y e t i d e n t i f i e d t r a n s p o r t e r ( 1 2 5 )
F u r t h e r r e s e a r c h i s n e e d e d
F e n t a n y l
P - g p
I n v i t r o :
S u b s t r a t e ( 1 2 6 ,
1 2 7 )
N o t a s u b s t r
a t e ( 3 3 )
I n v i v o :
S u b s t r a t e ( 5 1 ,
1 2 7 – 1 3 0 )
C l i n i c a l :
I n t e s t i n a l b u t n o t B B B s u b s t r a t e ( 1 3 1 )
1 2 3 6 T T , 2 6 7 7 T T , a n d 3 4 3 5 T T g e n o t y p e s l i n k e d w i t h i n c r e a s e d
f e n t a n y l - i n
d u c e d r e s p i r a t o r y d e p r e s s i o n ( 1 3 2 )
A B C B 1 p o l y
m o r p h i s m s h a v e n o e f f e c t o n f e n t a n y l - i n d u c e d
s e d a t i o n o r r e s p i r a t o r y d e p r e s s i o n ( 1 3 3 ) , o r c o m a / d e l i r i u m ( 1 3 4 )
C u r r e n t r o l e o f P - g p i s n o t c l e a r
O A T P
I n v i t r o :
N o t O A T P 1
B 1 s u b s t r a t e ( 1 3 5 )
I n v i v o :
S u b s t r a t e ( 1 3 6 )
C l i n i c a l :
N o t a s u b s t r
a t e ( 1 3 5 )
F e n t a n y l d o e s n o t a p p e a r t o b e
a n O A T P 1 B 1 s u b s t r a t e
Y e t i d e n t i f i e d
t r a n s p o r t e r a t B B B
I n v i t r o :
S u b s t r a t e a t
t h e B B B ( 1 2 6 )
M o r e r e s e a r c h i s n e e d e d i n t o t h i s t r a n s p o r t e r w h i c h
i n
v i t r o
e v i d e n c e s u g g e s t s p l a y s a m o r e p r o m i n e n t r o l e
t h a n P - g p i n o x y c o d o n e d i s p
o s i t i o n a t t h e B B B
M e t h a d o n e
P - g p
I n v i t r o :
S u b s t r a t e ( 3 2 ,
3 6 ,
1 1 1 ,
1 3 7 – 1 4 5 )
I n v i v o :
S u b s t r a t e ( 5 1 ,
1 1 1 ,
1 3 0 ,
1 4 6 – 1 4 8 )
C l i n i c a l :
S u b s t r a t e ( 1 4 9 – 1 5 1 )
P o s s i b l e i n t e s t i n a l ,
b u t n o t B B B s u b s t r a t e ( 1 3 1 )
U n l i k e l y s u b s t r a t e ( 9 5 ,
1 5 2 – 1 5 4 )
A B C B 1 p o l y
m o r p h i s m s i n f l u e n c e m e t h a d o n e d o s i n g ( 1 5 5 – 1
5 7 )
a n d P K ( 1
5 8 ,
1 5 9 )
A B C B 1 p o l y
m o r p h i s m s h a v e l i t t l e / n o i n f l u e n c e m e t h a d o n e
d o s i n g ( 1 6 0 – 1 6 2 ) o r P K ( 1 6 3 – 1 6 5 )
I n
v i t r o
a n d i n
v i v o
e v i d e n c e c l e a
r l y s u p p o r t m e t h a d o n e
a s a P - g p s u b s t r a t e ,
b u t c l i n i c
a l e v i d e n c e i s c o n f l i c t i n g .
T h e c u r r e n t r o l e o f P - g p i s u n c l e a r
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T a b l e I
( c o n t i n u e d )
D r u g N a m e
T r a n s p o r t e r
E v i d e n c e
C l i n i c a l i m p l i c a t i o n s
B u p r e n o r p h i n e
P - g p
I n v i t r o :
I n h i b i t o r : b u p r e n o r p h i n e a n d n o r b u p r e n o r p h i n e ( 3 6 )
S u b s t r a t e : n o r b u p r e n o r p h i n e ( 3 6 ,
1 6 6 )
N o t a s u b s t r
a t e : b u p r e n o r p h i n e ( 1 1 1 ,
1 6 6 ,
1 6 7 )
I n v i v o :
S u b s t r a t e : b u p r e n o r p h i n e ( 1 6 8 ) a n d n o r b u p r e n o r p h i n e ( 1 6 6
, 1 6 9 )
N o t a s u b s t r
a t e : b u p r e n o r p h i n e ( 1 1 1 )
C l i n i c a l :
N o t a s u b s t r
a t e ( 5 9 )
I n
v i t r o
a n d i n
v i v o
e v i d e n c e a p p
e a r t o s u g g e s t
b u p r e n o r p h i n e i s n o t , w h i l e
n o r b u p r e n o r p h i n e i s a
P - g p s u b s t r a t e .
O n e c l i n i c a l s t u d y a v a i l a b l e s u g g
e s t s b u p r e n o r p h i n e i s n o t
a P - g p s u b s t r a t e ( 5 9 ) , b u t t h i s f i n d i n g h a s b e e n
c o n t e s t e d b y o t h e r s ( 1 7 0 )
B C R P
I n v i t r o :
I n h i b i t o r : b u p r e n o r p h i n e a n d n o r b u p r e n o r p h i n e ( 3 6 )
L i m i t e d e v i d e n c e s u g g e s t s b u p r
e n o r p h i n e a n d
n o r b u p r e n o r p h i n e a r e B C R P i n h i b i t o r s .
T h i s c o u l d l e a d t o c l i n i c a l D D I s
w i t h l i k e l y B C R P
s u b s t r a t e s s u c h a