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. 2022 Jan;40(1):75-87.
doi: 10.1007/s11419-021-00595-6. Epub 2021 Aug 24.

Human and rat microsomal metabolites of N-tert-butoxycarbonylmethamphetamine and its urinary metabolites in rat

Hidenao Kakehashi  1 , Takahiro Doi  2 , Misato Wada  3 , Tooru Kamata  3 , Noriaki Shima  3 , Akari Miyake  3 , Atsushi Nitta  3 , Ryutaro Asai  3 , Shihoko Fujii  3 , Shuntaro Matsuta  3 , Keiko Sasaki  3 , Hiroe Kamata  3 , Hiroshi Nishioka  3 , Akihiro Miki  3 , Hiroshi Hasegawa  4 , Munehiro Katagi  3
Affiliations

Human and rat microsomal metabolites of N-tert-butoxycarbonylmethamphetamine and its urinary metabolites in rat

Hidenao Kakehashi et al. Forensic Toxicol. 2022 Jan.

Abstract

Purpose: N-tert-Butoxycarbonylmethamphetamine (BocMA), a masked derivative of methamphetamine (MA), converts into MA under acidic condition and potentially acts as a precursor to MA following ingestion. To investigate the metabolism and excretion of BocMA, metabolism tests were conducted using human liver microsomes (HLM), rat liver microsomes (RLM) and rat.

Methods: BocMA metabolites were analyzed after 1000-ng/mL BocMA incubation with microsomes for 3, 8, 13, 20, 30, and 60 min. Rats were administered intraperitoneal injections (20 mg/kg) of BocMA and their urine was collected in intervals for 72 h. Metabolites were detected by liquid chromatography-tandem mass spectrometry with five authentic standards.

Results: Several metabolites including 4-hydroxy-BocMA, N-tert-butoxycarbonylephedrine and N-tert-butoxycarbonyl-cathinone were detected for HLM and RLM. In the administration test, three glucuronides of hydroxylated metabolites were detected. The total recovery values of BocMA and the metabolites during the first 72 h accounted for only 0.3% of the administered dose. Throughout the microsomal and administration experiments, MAs were not detected.

Conclusion: Hydroxylation, carbonylation and N-demethylation were proposed as metabolic pathways. However, BocMA and phase I metabolites were hardly detected in urine. This study provides useful information to interpret the possibility of BocMA intake as the cause of MA detection in biological sample.

Keywords: LC–MS/MS; Metabolite; Methamphetamine; Microsomes; N-tert-Butoxycarbonylmethamphetamine; Rat.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Fig. 1
Fig. 1
A The extracted ion chromatograms of BocMA metabolites following incubation with human liver microsomes (HLM) and rat liver microsomes (RLM). B Product ion spectra of the microsomal metabolites (M1–6) and authentic standards (BocMA, BocMC)
Fig. 1
Fig. 1
A The extracted ion chromatograms of BocMA metabolites following incubation with human liver microsomes (HLM) and rat liver microsomes (RLM). B Product ion spectra of the microsomal metabolites (M1–6) and authentic standards (BocMA, BocMC)
Fig. 2
Fig. 2
Concentrations of BocMA and M1 (D1, 2) following incubation of 1000-ng/mL BocMA with human liver microsomes (HLM) and rat liver microsomes (RLM), n = 3
Fig. 3
Fig. 3
Extracted ion chromatograms and product ion spectra of M7, M8 and M9 in rat urine collected at the first 4 h form injection
Fig. 4
Fig. 4
Extracted ion chromatograms of M5 and M9 obtained from rat urine before and after hydrolysis
Fig. 5
Fig. 5
Proposed concept of BocMC hydration mechanism
Fig. 6
Fig. 6
Proposed metabolic scheme of BocMA for human and rat
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