Pharmacokinetics of heroin and its metabolites in vitreous humor and blood in a living pig model.

André Gottås,Liliana C Bachs,Gudrun Høiseth,Per Steinar Halvorsen,Marianne Arnestad

doi:10.1007/s11419-016-0315-z

Abstract

Vitreous humor (VH) is an alternative matrix for drug analysis in forensic toxicology. However, little is known about the distribution of xenobiotics, such as opioids, into VH in living organisms. The aim of this study was to simultaneously measure heroin and metabolite concentrations in blood and VH after injection of heroin in a living pig model. Six pigs were under non-opioid anesthesia during the surgical operation and experiment. Ocular microdialysis was used to acquire dialysate from VH, and a venous catheter was used for blood sampling. Twenty milligrams of heroin was injected intravenously with subsequent sampling of blood and dialysate for 6 h. The samples were analyzed by ultra-performance liquid chromatography–tandem mass spectrometry. Heroin was not detected in VH; 6-monoacetylmorphine (6-MAM) and morphine were first detected in VH after 60 min. The morphine concentration in VH thereafter increased throughout the experimental period. For 6-MAM, Cmax was reached after 230 min in VH. In blood, 6-MAM reached Cmax after 0.5 min, with a subsequent biphasic elimination phase. The blood and VH 6-MAM concentrations reached equilibrium after 2 h. In blood, morphine reached Cmax after 4.3 min, with a subsequent slower elimination than 6-MAM. The blood and VH morphine concentrations were in equilibrium about 6 h after injection of heroin. In conclusion, both 6-MAM and morphine showed slow transport into VH; detection of 6-MAM in VH did not necessarily reflect a recent intake of heroin. Because postmortem changes are expected to be small in VH, these experimental results could assist the interpretation of heroin deaths.

Highlights

Heroin is a highly lipid soluble opioid prodrug with negligible affinity and efficacy to l-opioid receptor [1,2,3]
Recoveries for each microdialysis probes in Vitreous humor (VH) were calculated by retrodialysis using isotope analogs as described by Gottas et al [11]
There was some inconsistency in the experimental period with sampling from the living animal, because it was prolonged as compared with the handling of postmortem samples, after we discovered the slow transfer to VH in the first pig

Summary

Introduction

Heroin is a highly lipid soluble opioid prodrug with negligible affinity and efficacy to l-opioid receptor [1,2,3]. Heroin is rapidly and completely converted to 6-monoacetylmorphine (6-MAM) spontaneously or by serum and tissue cholinesterases, and by tissue carboxyesterases, among others. The blood elimination half-life for heroin is less than 5 min, for 6-MAM around 15–20 min, for morphine 2–3 h, and for its glucuronides, 4–6 h [7]. The most intense phase of heroin effects, the ‘‘rush’’, takes place shortly after intake. At this stage 6-MAM is the predominant metabolite in both blood and brain [7,8,9,10]. 1–2 h after intake, morphine and M6G are the main metabolites able to mediate heroin’s effects

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