Blood pharmacokinetics and use of metabolite-to-parent ratios to predict time of last Zopiclone intake

Zopiclone (ZOP) is a sedative-hypnotic drug that is featured commonly in impaired driving, drug-facilitated crimes, accidental overdose, or suicidal intoxications. Further understanding of its blood pharmacokinetics would support its interpretation in forensic toxicology casework. This study characterizes the concentration-time pharmacokinetic profiles of ZOP and its metabolite N-desmethyl-zopiclone (N-DMZOP) in blood following controlled administration, and evaluates the use of metabolite-to-parent ratios in estimating time of last ZOP intake. Sixteen subjects received a single oral dose of either 5 mg or 10 mg Imovane®, and blood samples were collected pre-dosing, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 24 and 48- hours post-dose. A paired plasma sample was also provided at the 2-hour time point. A previously validated LC-MS/MS method was used to quantify ZOP, N-DMZOP and the degradation product 2-amino-5-chloropyridine (ACP). The aggregate regression model developed from this younger subject population was applied to independently dosed subjects, and a separate group of elderly patients to determine the validity of this model in an older cohort of differing pharmacokinetic characteristics. Comparison between the 5 mg and 10 mg dosing groups supported a linear-dose concentration relationship. While the ratio of N-DMZOP/ZOP can be a predictive indicator for time of ZOP intake, inter-individual differences in ZOP disposition may influence such predictions. Furthermore, age-related pharmacokinetic changes may contribute to a general underestimation of predicted time with the current model, but a larger sample size of a broader demographic spectrum and dosing regimen would help improve the general applicability of this ratio-based modelling. Finally, we show that the mean blood-to-plasma ratio for ZOP and N-DMZOP were 0.79 and 0.92, respectively, suggesting a preferential partitioning of ZOP into the plasma fraction, which would be a useful reference when interpreting plasma concentrations from clinical studies against the more routinely sampled whole blood concentrations found in forensic toxicological casework.