Metabolism of Butyrylfentanyl in Fresh Human Hepatocytes: Chemical Synthesis of Authentic Metabolite Standards for Definitive Identification.

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Kanamori T, Iwata YT, Segawa H, Yamamuro T, Kuwayama K, Tsujikawa K, Inoue H

Metabolism of Butyrylfentanyl in Fresh Human Hepatocytes: Chemical Synthesis of Authentic Metabolite Standards for Definitive Identification.

Biol Pharm Bull. 2019;42(4):623-630. doi: 10.1248/bpb.b18-00765.

PubMed ID

30930421 [ View in PubMed

]

Abstract

The metabolism of butyrylfentanyl, a new designer drug, was investigated using fresh human hepatocytes isolated from a liver-humanized mouse model. In the culture medium of hepatocytes incubated with butyrylfentanyl, the desphenethylated metabolite (nor-butyrylfentanyl), omega-hydroxy-butyrylfentanyl, (omega-1)-hydroxy-butyrylfentanyl, 4'-hydroxy-butyrylfentanyl, beta-hydroxy-butyrylfentanyl, 4'-hydroxy-3'-methoxy-butyrylfentanyl, and omega-carboxy-fentanyl were identified as the metabolites of butyrylfentanyl. Each metabolite was definitively identified by comparing the analytical data with those of authentic standards. The amount of the main metabolite, nor-butyrylfentanyl, reached 37% of the initial amount of butyrylfentanyl at 48 h. omega-Hydroxy-butyrylfentanyl and (omega-1)-hydroxy-butyrylfentanyl, formed by hydroxylation at the N-butyryl group of butyrylfentanyl, were the second and third largest metabolites, respectively. The majority of 4'-hydroxy-butyrylfentanyl and 4'-hydroxy-3'-methoxy-butyrylfentanyl was considered to be conjugated. CYP reaction phenotyping for butyrylfentanyl using human liver microsomes and various anti-CYP antibodies revealed that CYP3A4 was involved in the formation of nor-butyrylfentanyl, (omega-1)-hydroxy-butyrylfentanyl, and beta-hydroxy-butyrylfentanyl. In contrast, CYP2D6 was involved in the formation of omega-hydroxy-butyrylfentanyl.

DrugBank Data that Cites this Article

Drugs

Butyrfentanyl

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Butyrfentanyl	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate	Details
Butyrfentanyl	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details

Drug Reactions

Reaction
Butyrfentanyl DB09173 Cytochrome P450 3A4 Cytochrome P450 2D6 nor-butyrfentanyl DBMET02688	Details
Butyrfentanyl DB09173 Cytochrome P450 3A4 (ω-1)-hydroxy-butyrfentanyl DBMET02689	Details
Butyrfentanyl DB09173 Cytochrome P450 3A4 β-hydroxy-butyrfentanyl DBMET02690	Details
Butyrfentanyl DB09173 4'-hydroxy-butyrfentanyl DBMET02691	Details
Butyrfentanyl DB09173 Cytochrome P450 2D6 Cytochrome P450 3A4 ω-hydroxy-butyrfentanyl DBMET02693	Details