Postmortem drug concentrations do not necessarily reflect concentrations at the time of death, as drug levels may vary according to the sampling site and the interval between death and specimen collection. These site- and time-dependent variations are called “postmortem redistribution” (PMR). The underlying mechanisms are complex and of different types. Passive drug release from drug reservoirs such as the gastrointestinal tract, liver, lungs, and myocardium may occur immediately after death and, later on, cell autolysis and the putrefactive process participate in redistribution. There is evidence that basic lipophilic drugs with a large distribution volume are particularly susceptible to PMR. Nevertheless, this cannot explain the actual PMR of some nonbasic, nonlipophilic drugs. In addition, the persistence of drug metabolism immediately after death must be considered. Consequently, it is of great importance to analyze specimens from different sampling sites in order to detect potential PMR and avoid misinterpretation of results.

The goal of this study was to evaluate the specific contribution of individual UDP-glucuronosyltransferase (UGT) isoforms in the metabolism of buprenorphine (BUP) and norbuprenorphine (Nor-BUP), as well as the impact of their genetic variations. The glucuronidation of BUP and Nor-BUP was examined using human liver microsomes (HLMs) and heterologously expressed UGTs. The individual contribution of UGT isoforms was estimated using enzyme kinetic experiments combined with the relative activity factor (RAF). Phenotype-genotype relationships were investigated in a bank of 52 HLMs. Among the six hepatic UGT isoforms tested, UGT1A1, UGT1A3, and UGT2B7 metabolized BUP and Nor-BUP. Using the RAF approach, we found that UGT1A1 and UGT2B7 accounted for approximately 10 and 41% of BUP glucuronidation, respectively. Nor-BUP glucuronidation involved predominantly UGT1A3 (approximately 63%) and UGT1A1 (34%), whereas UGT2B7 had only a minor role. The UGT1A1 promoter (TA)_6/7TAA mutation (UGT1A1*28) resulted in a 28% decrease of BUP glucuronidation V_max in pooled HLMs but was not statistically associated with glucuronidation rate in 52 individual HLMs. The presence of the UGT2B7 promoter (G–842A) mutation resulted in higher BUP glucuronidation V_max in pooled HLMs (+80% on average) and in a significant higher glucuronidation rate in noncarriers (but not in carriers) of the UGT1A1*28 allele (P = 0.0352). This study represents a functional basis for further clinical pharmacogenetic studies.