Abstract
In this study, the biotransformation in the plasma, urine and feces of rats following oral administration of protopine (PRO) and allocryptopine (ALL)were explored using HPLC-QqTOF MS. An HPLC-MS/MS method for the determination of tissues was developed and applied to the tissue distribution study in rats following intragastric administration of Plume Poppy Total Alkaloid for 3 weeks. A total of ten PRO metabolites and ten ALL metabolites were characterized in rats in vivo. Among these metabolites, six PRO metabolites and five ALL metabolites were reported for the first time. The predicated metabolic pathways including ring cleavage, demethylation following ring cleavage, and glucuronidation were proposed. The low-concentration residue of PRO and ALL in various tissues was detected at 24 h and 48 h after dosing, which indicated that both compounds could be widely distributed in tissues and exist as low levels of residue. The activities of erythromycin N-demethylase, aminopyrine N-demethylase and NAD (P)H quinone oxidoreductase in female rats can be induced post-dose, but these activities were inhibited in male rats. The proposed biotransformation and residues of PRO and ALL and their effects on enzymes may provide a basis for clarifying the metabolism and interpreting pharmacokinetics.
Highlights
The isoquinoline alkaloids protopine (PRO) and allocryptopine (ALL) are found primarily in the plant families Fumariaceae, Papaveraceae, Berberidaceae and Ranunculaceae[1,2,3,4,5]
We developed an HPLC-QqTOF mass spectrometry (MS) method to characterize the metabolites formed by accurate mass measurements of MS and MS2 spectra and a high-performance liquid chromatography/triple-quadrupole mass (HPLC-MS/MS) method to quantify ALL and PRO in rat liver, kidney, spleen, lung and heart
The accurate extracted ion chromatograms (EIC) of female rat urine between 0 h and 24 h after oral administration of a single dose of PRO are shown in Fig. S1. (See supplemental material)
Summary
The isoquinoline alkaloids protopine (PRO) and allocryptopine (ALL) are found primarily in the plant families Fumariaceae, Papaveraceae, Berberidaceae and Ranunculaceae[1,2,3,4,5]. Both are biologically active substances in human and veterinary phytopreparations from medicinal plants such as Chelidonium majus and Macleaya cordata[6]. Inhibition studies on rat liver microsomes indicated that CYP2D1 and CYP2C11 were primarily involved in demethylenation of PRO, while CYP1A2 and CYP3A2 showed only minor contributions[22]. The effects of PRO and ALL on drug-metabolizing enzymes in vivo have not been assessed to date
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