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Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

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Abstract

Opioid-related deaths, abuse, and drug interactions 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, pharmacodynamics 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 prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

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Abbreviations

6-MAM:

6-monoacetylmorphine

AAPCC:

American Association for Poison Control Centers

AUC:

Area under the curve

BBB:

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

Ki :

Inhibition constant

Kp,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

Vu,brain :

Volume of distribution within the brain

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Rooms: N525 (Office), Baltimore, Maryland, 21201, USA

    Robert Gharavi, William Hedrich, Hongbing Wang & Hazem E. Hassan

  2. Clinical Development, MedImmune, One MedImmune Way, Gaithersburg, Maryland, 20878, USA

    Robert Gharavi

  3. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo, Egypt

    Hazem E. Hassan

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  1. Robert Gharavi
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Gharavi, R., Hedrich, W., Wang, H. et al. Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions. Pharm Res 32, 2477–2502 (2015). https://doi.org/10.1007/s11095-015-1711-5

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