siRNA capsulated brain-targeted nanoparticles specifically knock down OATP2B1 in mice: a mechanism for acute morphine tolerance suppression

Yang, Zi Zhao; Li, Li; Wang, Lu; Xu, Ming; An, Sai; Jiang, Chen; Gu, Jing; Wang, Zai Jie Jim; Yu, Liping; Zeng, Su

doi:10.1038/srep33338

Cited by 15 publications

(13 citation statements)

References 47 publications

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“…The cause for the lower M3G levels in the plasma of KO mice than plasma from WT mice, while M3G contents were similar in WT and KO brain and spinal cord, may be further explored. The difference in plasma M3G may be due to alterations in morphine metabolism 44 by glucuronyl transferases 50 , pharmacokinetics, passage through the blood-brain barrier through ATP-binding cassette transporters 51 or organic anion transporting polypeptides 52 , as well as elimination 44 . Altogether our results suggest that some differences in M3G signalling compared to other opioid agonists could explain why this molecule displays hyperalgesic rather than analgesic activity.…”

Section: Discussionmentioning

confidence: 99%

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide

Roeckel

Utard

Reiss

et al. 2017

Sci Rep

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Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G-protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G.

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Section: Discussionmentioning

confidence: 99%

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide

Roeckel

Utard

Reiss

et al. 2017

Sci Rep

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“…14 To avoid overparameterization, the model focused on the major transporters for morphine (OCT1) and M3G (MRP2 and MRP3). However, in vitro data indicate that morphine also is a substrate of OATP2B1, 46 and clinical data suggest that P-glycoprotein may affect morphine absorption. 47 Therefore, inclusion of these transporters could be important for modeling oral dosing data, which was not the focus in this study.…”

Section: Articlementioning

confidence: 99%

Physiologically‐Based Pharmacokinetic Model of Morphine and Morphine‐3‐Glucuronide in Nonalcoholic Steatohepatitis

Sjöstedt

Brouwer

2020

Clin Pharma and Therapeutics

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Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease, is increasing in prevalence. NASH‐related alterations in hepatic protein expression (e.g., transporters) and in overall physiology may affect drug exposure by altering drug disposition and elimination. The aim of this study was to build a physiologically‐based pharmacokinetic (PBPK) model to predict drug exposure in NASH by incorporating NASH‐related changes in hepatic transporters. Morphine and morphine‐3‐glucuronide (M3G) were used as model compounds. A PBPK model of morphine with permeability‐limited hepatic disposition was extended to include M3G disposition and enterohepatic recycling (EHR). The model captured the area under the plasma concentration‐time curve (AUC) of morphine and M3G after intravenous morphine administration within 0.82‐fold and 1.94‐fold of observed values from 3 independent clinical studies for healthy adult subjects (6, 10, and 14 individuals). When NASH‐related changes in multidrug resistance‐associated protein 2 (MRP2) and MRP3 were incorporated into the model, the predicted M3G mean AUC in NASH was 1.34‐fold higher compared to healthy subjects, which is slightly lower than the observed value (1.63‐fold). Exploratory simulations on other physiological changes occurring in NASH (e.g., moderate decreases in glomerular filtration rate and portal vein blood flow) revealed that the effect of transporter changes was most prominent. Additionally, NASH‐related transporter changes resulted in decreased morphine EHR, which could be important for drugs with extensive EHR. This study is an important first step to predict drug disposition in complex diseases such as NASH using PBPK modeling.

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“…Although OATP1A2 has also been detected in the intestine, data concerning its relevance in intestinal drug uptake are controversial . On the other hand, there is increasing evidence that OATP1A2 plays an important role in drug penetration into the CNS by regulating drug entry into the BBB endothelial cells and also in drug absorption/re‐absorption in the bile duct and in the kidney . Endogenous substrates of OATP1A2 include bile acids, bilirubin, steroid and thyroid hormones, prostaglandin E2, and all‐trans‐retinol .…”

Section: Introductionmentioning

confidence: 99%

A novel fluorescence‐based functional assay for human OATP1A2 and OATP1C1 identifies interaction between third‐generation P‐gp inhibitors and OATP1A2

et al. 2019

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Organic anion‐transporting polypeptide 1A2 (OATP1A2), expressed in the human blood–brain barrier, promotes drug uptake from the blood and hence can be exploited for central nervous system‐targeted drug delivery. The thyroid transporter OATP1C1, expressed in the choroid plexus and in astrocytes, is also a potential pharmacological target. Based on their established pharmacological relevance, screening the drug interaction profile of OATP1A2 and OATP1C1 is highly desirable. However, drug interaction screens require suitable model systems and functional assays. In the current study, uptake of a set of cell‐impermeable fluorescent dyes was screened in HEK‐293 and A431 cell lines overexpressing OATP1A2 and OATP1C1. Based on the uptake of fluorescent dye substrates, a functional assay was developed, which was used to characterize OATP inhibitors/substrates. We identify Live/Dead Green (LDG), Live‐or‐Dye 488, and sulforhodamines 101, G, and B as novel fluorescent substrates of OATP1A2 and OATP1C1. We show that LDG uptake is proportional to OATP1A2/1C1 expression, allowing the isolation of cells expressing high transporter levels. Additionally, dye uptake can be used to characterize the drug interaction pattern of OATP1A2 and OATP1C1. We demonstrate that third‐generation P‐glycoprotein inhibitors elacridar, tariquidar, and zosuquidar inhibit OATP1A2 function. Increased toxicity of elacridar in OATP1A2‐expressing cells suggests that OATP1A2 may modulate the distribution of this compound. The fluorescence‐based assays developed in the current study are a good alternative of radioligand‐based tests and pave the way toward high‐throughput screens for OATP1A2/1C1 drug interaction studies.

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siRNA capsulated brain-targeted nanoparticles specifically knock down OATP2B1 in mice: a mechanism for acute morphine tolerance suppression

Cited by 15 publications

References 47 publications

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide

Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide

Physiologically‐Based Pharmacokinetic Model of Morphine and Morphine‐3‐Glucuronide in Nonalcoholic Steatohepatitis

A novel fluorescence‐based functional assay for human OATP1A2 and OATP1C1 identifies interaction between third‐generation P‐gp inhibitors and OATP1A2

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