Introduction: AH-7921 is a synthetic opioid, possibly associated to non-fatal intoxications and even deaths. Several metabolites were found in blood and urines of AH-7921 users, as well as in in vitro studies. No data are however available as regards the pharmacokinetic profile, in particular in the brain, of AH-7921 and its metabolites. Methods: Rats were treated intraperitoneally with 10 mg/kg AH-7921. Brain and plasma metabolites were firstly identified by an high resolution mass spectrometry LTQ-Orbitrap XL. Determination of drug concentrations, and semi-quantitative analysis of the main metabolites, were obtained by HPLC-MS/MS, using a triple quadrupole with ESI positive ionization in MRM mode. Results: Cmax was reached 30 min after treatment, either in plasma (205 ng/mL on average) and brain (2842 ng/g), with a brain-to-plasma ratio of ~20. Plasma and brain levels then declined with a similar t1/2 (~ 3 hours). Different metabolites (N-desmethylated, N-didesmethylated, hydroxylated, N-desmethylated hydroxylated and N-didesmethylated hydroxylated) were detected in plasma and brain already 5 minutes after dose and at the following time-points. In particular, the first two reached, at longer time-points, brain levels comparable or even higher than those of the parent compound. Notably, the N-didesmethylated metabolite showed a very slow elimination from brain tissue. Conclusions: The new psychoactive drug AH-7921, as well as its main metabolites, readily reach the brain with brain-to-plasma ratios of ~15-20. The pharmacokinetic data obtained for the two main metabolites suggests the need of a further characterization of their pharmacological activities, as well as of similar studies after repeated treatments.
Evaluation of the brain-to-plasma distribution of AH-7921 and semi-quantitative analysis of its main metabolites in rats
Claudio Marcello Marzo;
2016-01-01
Abstract
Introduction: AH-7921 is a synthetic opioid, possibly associated to non-fatal intoxications and even deaths. Several metabolites were found in blood and urines of AH-7921 users, as well as in in vitro studies. No data are however available as regards the pharmacokinetic profile, in particular in the brain, of AH-7921 and its metabolites. Methods: Rats were treated intraperitoneally with 10 mg/kg AH-7921. Brain and plasma metabolites were firstly identified by an high resolution mass spectrometry LTQ-Orbitrap XL. Determination of drug concentrations, and semi-quantitative analysis of the main metabolites, were obtained by HPLC-MS/MS, using a triple quadrupole with ESI positive ionization in MRM mode. Results: Cmax was reached 30 min after treatment, either in plasma (205 ng/mL on average) and brain (2842 ng/g), with a brain-to-plasma ratio of ~20. Plasma and brain levels then declined with a similar t1/2 (~ 3 hours). Different metabolites (N-desmethylated, N-didesmethylated, hydroxylated, N-desmethylated hydroxylated and N-didesmethylated hydroxylated) were detected in plasma and brain already 5 minutes after dose and at the following time-points. In particular, the first two reached, at longer time-points, brain levels comparable or even higher than those of the parent compound. Notably, the N-didesmethylated metabolite showed a very slow elimination from brain tissue. Conclusions: The new psychoactive drug AH-7921, as well as its main metabolites, readily reach the brain with brain-to-plasma ratios of ~15-20. The pharmacokinetic data obtained for the two main metabolites suggests the need of a further characterization of their pharmacological activities, as well as of similar studies after repeated treatments.
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