Predicting the efficacy of opioid sequestration by intravenous lipid emulsion using biologically relevant in vitro models of drug distribution

Abstract

Intravenous lipid emulsions (ILE), among other uses, are utilized in the treatment of poisonings caused by lipophilic substances. The body of evidence regarding the benefits of this treatment is growing but information about opioids-ILE interaction is still very scarce. In this work, the impact of ILE on the distribution of buprenorphine, fentanyl and butorphanol used in various concentrations (100–500 ng/ml) was investigated. Two different in vitro models were used: disposition of the drugs in plasma after ultracentrifugation and distribution into the simulated biophase (cell monolayer of 3T3 fibroblasts or J774.E macrophages). We confirmed the ability of ILE to sequester the three drugs of interest which results in their decrease in the aqueous part of the plasma by 34.2–38.2%, 11.7–28.5% and 6.0–15.5% for buprenorphine, fentanyl and butorphanol, respectively. Moreover, ILE affected the drug distribution to the biophase in vitro, however, in this case the drug concentration in cells decreased by 97.3 ± 3.1%, 28.6 ± 5.4% and 13.0 ± 7.5% for buprenorphine, fentanyl and butorphanol, respectively. The two models revealed notable differences in ILE’s potential for drug sequestration, especially for buprenorphine. Similar, but not as pronounced tendencies were observed for the two other drugs. These discrepancies may result from the difference in protein abundance and resulting drug-protein binding in both systems. Nevertheless, the results obtained with both in vitro models correlated well with the partition coefficient (logP) values for these drugs.

Lipid Emulsion to Treat Acute Poisonings: Mechanisms of Action, Indications, and Controversies

“…ILE has been reported to reverse the toxicity caused by drugs lacking any common mechanism, site of action, chemical structure, or clinical effects except lipophilicity [6]. The partitioning effect is in accordance with lipid dialysis therapy [11], and has been demonstrated in numerous in vitro studies [36][37][38][39][40]. French et al measured the amount of several drugs sequestered in vitro from human serum using Intralipid ® [41].…”

Nanotherapeutics for Alleviating Anesthesia‐Associated Complications

“…Other detoxifying effects mainly stem from the bioactivity of lipids, including enhanced energy provision and cardiotonic and vasoconstrictive abilities. [13,[105][106][107] Based on the lipid sequestration and redistribution mechanism, several preclinical studies and case reports have suggested the application of lipid emulsion to detoxify other hydrophilic anesthetic drugs such as propofol, cocaine and tramadol. [108][109][110] However, there are still discrepancies regarding the effectiveness and widespread application of lipid rescue therapy.…”

Biomedical Nanosystems for <i>in vivo</i> Detoxification: From Passive Delivery Systems to Functional Nanodevices and Nanorobots

“…Lipid emulsion resuscitation therapy is recommended for the treatment of lipophilic drug overdoses; specifically, lipid emulsions (LE) are administered intravenously as non-specific antidotes, in the form of an "oil-in-water" type of drops [ 35 ]. LEs have been used for overdose treatment and to reduce the concentration of lipophilic antiarrhythmic, psychotropic, antimalarial drugs, local anesthetics, calcium channel blockers such as propranolol [ 36 ], cocaine [ 37 , 38 ], diltiazem [ 39 ], buprenorphine, fentanyl and butorphanol [ 40 ], bupivacaine [ 41 ], ivermectin [ 42 , 43 ], and ropivacaine [ 44 , 45 ]. LEs rapidly decrease the threshold for seizure activity, amoxapine toxicity [ 46 ], and improve cardiac activity during heart transplantation [ 47 ].…”

“…Известно, что при передозировке липофильных препаратов рекомендуется применение липидной реанимационной терапии, а именно, использование в качестве неспецифических антидотов липидных эмульсий (ЛЭ) -внутривенно вводимых наноразмерных капель типа «масло в воде» [35]. ЛЭ применяют при передозировке и для снижения концентрации липофильных антиаритмических, психотропных, противомалярийных препаратов, местных анестетиков, блокаторов кальциевых каналов, таких, как пропранолол [36], кокаин [37,38], дилтиазем [39], бупренорфин, фентанил и буторфанол [40], бупивакаин [41], ивермектин [42,43], ропивакаин [44,45]. Использование ЛЭ быстро снижает порог судорожной активности, токсичности амоксапина [46], улучшает сердечную деятельность при трансплантации сердца [47].…”