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

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.

Postmortem tissue distribution of morphine and its metabolites in a series of heroin‐related deaths

“…These results in vitreous when compared to femoral blood are in agreement with a previous study (R 2 = 0.26; n = 40, 61 as are the results of femoral blood to cardiac blood (R 2 = 0.76) and psoas muscle (R 2 = 0.75) 16 but do not agree with the results of two other studies that showed significant correlations between femoral blood and vitreous concentrations (R 2 = 0.87; p < 0.01, n = 69 62 ), (R 2 = 0.72; p < 0.001, n = 52 60 ), and (R 2 = 0.79; p > 0.001, n = 45 16 ). The differing sets of results obtained by the various groups and this study show that although correlations may exist for populations due to differences such as individual tolerance, individual metabolism, survival time after the administration of the drug, and also postmortem redistribution, 63,64 in the absence of a femoral blood sample in a case other samples should not be used to attempt to determine the femoral blood concentration.…”

Morphine Accumulates in the Retina Following Chronic Systemic Administration

“…As previously mentioned, opioid metabolites are routinely detected from postmortem human VH samples; however, these samples are often collected from overdose victims following the administration of a fatal opioid dose [ 26 , 28 , 29 , 30 , 31 , 32 ]. While it is unclear whether sub-lethal opioid doses similarly accumulate in human VH/retina, animal studies suggest that sub-lethal doses of opioids accumulate in the mammalian VH/retina following systemic exposure [ 11 , 31 , 47 ].…”

“…As previously mentioned, opioid metabolites are routinely detected from postmortem human VH samples; however, these samples are often collected from overdose victims following the administration of a fatal opioid dose [ 26 , 28 , 29 , 30 , 31 , 32 ]. While it is unclear whether sub-lethal opioid doses similarly accumulate in human VH/retina, animal studies suggest that sub-lethal doses of opioids accumulate in the mammalian VH/retina following systemic exposure [ 11 , 31 , 47 ]. While the current study differs in species, treatment, and methodology, it builds on this past work by providing an examination of morphine pharmacokinetics within mouse retina following both acute and repeated systemic morphine administration.…”

“…In forensic toxicology, the vitreous humor (VH) of the eye is often used to determine if an opioid overdose contributed to fatality [ 26 , 28 , 29 , 30 , 31 , 32 ]. Opioid drugs/metabolites in the VH are protected from postmortem degradation and redistribution, making it an ideal sample for postmortem toxicological investigations [ 26 , 28 , 29 , 32 ].…”

“…Opioid drugs/metabolites in the VH are protected from postmortem degradation and redistribution, making it an ideal sample for postmortem toxicological investigations [ 26 , 28 , 29 , 32 ]. Since these VH samples are mostly collected postmortem from victims of opioid-related deaths, the pharmacokinetics of opioid drugs within the VH are relatively poorly understood compared to other tissues such as the brain and blood [ 9 , 11 , 28 , 29 , 31 , 33 , 34 ]. Thus, the mechanism that underlies the persistence of opioid drugs (and their metabolites) in the VH is unclear [ 26 , 35 ].…”