Effects of Alcohol on the Pharmacokinetics of Fentanyl and Norfentanyl in Conscious Rat Plasma and Nucleus Accumbens

摘要

Objective:Fentanyl is generally used clinically as a pain reliever and an anesthetic, while overdose can lead to severe addiction or death. As reported in the case, other psychoactive substances（like alcohol） have been found in fentanyl deaths. This study was aimed to investigate the effects of alcohol on the pharmacokinetic characteristics of fentanyl and norfentanyl in plasma and nucleus accumbens（NAc） of conscious rats. Methods: The pharmacokentics of fentanyl and norfentanyl in rat NAc were assessed via brain mocrodialysis after oral administration of alcohol（3.5 g/kg alcohol, p.o.）, while the control group was given 20 μg/kg fentanyl（i.v.） after oral administration of an equal volume of water. In addition, plasma levels of these analytes were also evaluated. The plasma samples were extracted by Methyltert-butylether（MTBE） and constituted in, and then liquid chromatography–tandem mass spectrometry（LC–MS-MS） was applied for detection in positive mode and multiple-reaction monitoring（MRM）. Separation was performed on the C₁₈ column（100 × 2.1 mm, particle size 1.7 μm） with mobile phase of 0.1 % aqueous formic acid and acetonitrile. Results: This method was comprehensively validated. The limit of detection was 2 pg/mL（S/N>10） for both fentanyl and norfentanyl. For fentanyl pharmacokinetics in rat plasma, the obtained mean residence time（MRT） values were（135.54 ± 31.27） min in the model group（with alcohol） and（91.39 ± 13.51） min in the control group（without alcohol）, showing a significant difference（P < 0.01）. A similar huge gap of T1/2 could also be seen between groups, with（197.34 ± 32.04） min in the model group and（119.27 ± 17.73） min in the control group. Besides, the Vz/F value of the model group was twice that of the control group（11.93 ± 2.86 vs 6.25 ± 1.25 L/kg）. Regarding norfentanyl, exposure in plasma after dosing alcohol increased from about 70 μg/min/L to 100 μg/min/L. The MRT, T_max and T_1/2 of norfentanyl also postponed about 60 min. Meanwhile, compared with the control group, the exposure of fentanyl(AUC_0-∞ and C_max) in the rat NAc increased more than three times after alcohol consumption. The MRT of fentanyl in the rat NAc were changed by alcohol（89.87 ± 49.11 vs 102.87 ± 25.16 min）. Conclusion: The pharmacokinetic characteristics of fentanyl and norfentanyl in the plasma and NAc of rats were altered, with increased distribution in NAc after alcohol exposure. These results could assist forensic scientists to assess the risks of taking fentanyl after drinking alcohol and guide rational clinical use of fentanyl.

关键词

fentanyl / alcohol / nucleus accumbens / brain mocrodialysis / pharmacokinetic