1. transporter-mediated disposition of opioids implications for clinical drug interactions

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


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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 :



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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


E v i d e n c e


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



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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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



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 )



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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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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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

1. transporter-mediated disposition of opioids implications for clinical drug interactions

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