Pharmacokinetics, Tissue Distribution and Excretion of Demethyleneberberine, a Metabolite of Berberine, in Rats and Mice

Abstract

Demethyleneberberine is an active component extracted from the Chinese herbal drug Cortex Phellodendri. It is also a metabolite of berberine in animals and humans. However, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine have not been reported. The present study aimed to investigate the pharmacokinetic parameters of demethyleneberberine by applying high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). After intragastric administration of demethyleneberberine in rats and mice, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine were comparatively studied for the first time. The plasma concentration of demethyleneberberine reached its peak within 5 min after intragastric administration in both rats and mice. Furthermore, its bioavailability was comparable, ranging from 4.47% to 5.94%, higher than that of berberine. The total excretion of demethyleneberberine in the urine, feces and bile was 7.28~9.77%. These findings provide valuable insights into the pharmacological and clinical research on demethyleneberberine.

Keywords: demethyleneberberine; excretion; pharmacokinetics; rats and mice; tissue distribution.

Figure 1

(A) Chemical structures of demethyleneberberine and its mass spectra of [M + H]⁺ and (B) its mass spectra of product ions; (C) chemical structures of SNX-2112 and its mass spectra of [M + H]⁺ and (D) its mass spectra of product ions. (Arrows: precursor and product ions of Demethyleneberberine and SNX-2112, respectively).

Figure 2

Representative extraction MRM chromatograms of demethyleneberberine (DMB) and IS in plasma, heart, liver, brain, spleen, lung, kidney, stomach, intestine, bile, urine and feces. (A) Blank biological samples and blank biological sample spiked with LLOQ (lower limit of quantification) of DMB in plasma (0.5 ng/mL); heart, liver, brain, spleen, lung, kidney, intestine and urine (1 ng/mL); stomach, bile and feces (3 ng/mL); (B) blank biological samples spiked with DMB (300 ng/mL for plasma, heart, liver, brain, spleen, lung, kidney, stomach, intestine, bile, urine and feces) and IS (40 ng/mL); (C) test samples obtained after intragastric administration of DMB (40 mg/kg, at 30 min for plasma, heart, liver, brain, spleen, lung and kidney; 4 h for stomach and intestine; 6 h for bile and urine; and 36 h for feces) and IS (40 ng/mL) in rats; iso–the isomer of DMB.

Figure 2

Representative extraction MRM chromatograms of demethyleneberberine (DMB) and IS in plasma, heart, liver, brain, spleen, lung, kidney, stomach, intestine, bile, urine and feces. (A) Blank biological samples and blank biological sample spiked with LLOQ (lower limit of quantification) of DMB in plasma (0.5 ng/mL); heart, liver, brain, spleen, lung, kidney, intestine and urine (1 ng/mL); stomach, bile and feces (3 ng/mL); (B) blank biological samples spiked with DMB (300 ng/mL for plasma, heart, liver, brain, spleen, lung, kidney, stomach, intestine, bile, urine and feces) and IS (40 ng/mL); (C) test samples obtained after intragastric administration of DMB (40 mg/kg, at 30 min for plasma, heart, liver, brain, spleen, lung and kidney; 4 h for stomach and intestine; 6 h for bile and urine; and 36 h for feces) and IS (40 ng/mL) in rats; iso–the isomer of DMB.

Figure 3

Plasma concentration–time course of demethyleneberberine (a semi–log graph) in rats after a single (A) i.v. dose of 2.0 mg/kg or (B) i.g. dose of 20 or 40 mg/kg; in mice after a single (C) i.v. dose of 2.0 mg/kg or (D) i.g. dose of 40 mg/kg. Data are presented as mean ± SD (n = 5 or 15).

Figure 4

Tissue distribution of demethyleneberberine, (A) in rats after a single i.g. dose of 40 mg/kg; (B) in mice after a single i.g. dose of 40 mg/kg. Data are presented as mean ± SD (n = 5).

Figure 5

(A) Biliary, urinary and (B) fecal cumulative excretion of demethyleneberberine in rats after a single i.g. dose of 40 mg/kg; (C) urinary and (D) fecal cumulative excretion of demethyleneberberine in mice after a single i.g. dose of 40 mg/kg. Data are presented as mean ± SD (n = 5 or 9).