Pharmacokinetics and tissue distribution of monotropein and deacetyl asperulosidic acid after oral administration of extracts from Morinda officinalis root in rats

Abstract

Background: Iridoid glycosides (IGs), including monotropein (MON) and deacetyl asperulosidic acid (DA) as the main ingredients, are the major chemical components in Morinda officinalis How. (MO) root, possessing various pharmacological properties including anti-osteoporosis, anti-inflammation and anti-rheumatism activities.The aim of the present study was to further elucidate the pharmacological actions of MO by investigating the pharmacokinetics and tissue distribution of IGs in MO.

Methods: An ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) method was developed and validated for simultaneous determination of MON and DA levels in plasma and various tissues of Wistar rats. MON, DA and acetaminophen (ACE) as the internal standard (IS) were extracted from rat plasma and tissue samples by direct deproteinization with methanol. The rats were administered orally at 1650 mg/kg MO and 25, 50 and 100 mg/kg MO iridoid glycosides (MOIGs) or intravenously at MOIG 25 mg/kg for pharmacokinetic study of MON and DA. In addition, 100 mg/kg MOIG was administered orally for tissue distribution study of MON and DA. Non-compartmental pharmacokinetic profiles were constructed. Tissue distributions were calculated according to the validated methods.

Results: Significant differences in the pharmacokinetic parameters were observed in male and female rats. The AUC_0-t, C_max and bioavailability of MON and DA in female rats were higher than those in male rats. MON and DA mainly distributed in the intestine and stomach after oral administration, and noteworthily high concentrations of MON and DA were detected in the rat hypothalamus.

Conclusion: The results of the present study may shed new lights on the biological behavior of MOIGs in vivo, help explain their pharmacological actions, and provide experimental clues for rational clinical use of these IGs extracted from the MO root.

Keywords: Iridoid glycosides; Morinda officinalis; Pharmacokinetics; Tissue distribution; UPLC-MS/MS.

Fig. 1

Product ions and structures of MON (a), DA (b), and IS (c)

Fig. 2

Representative chromatograms of analytes from rat plasma and tissue. Blank plasma and tissue sample: (a) plasma, (b) liver, (c) stomach, (d) kidney, (e) uterus, (f) heart, (g) small intestine, (h) large intestine, (i) spleen, (j) lung, (k) thymus, (l) hypothalamus, (m) ovary, (n) testis, and (o) marrow. (p) actual sample plasma at 2 h after orally administration of 100 mg/kg MOIG, (q) hypothalamus sample obtained at 2 h after oral administration of 100 mg/kg MOIG, and (r) was IS (10 ng/mL). Peak 1 was MON and peak 2 was DA, and peak 3 was acetaminophen (IS)

Fig. 3

The mean plasma concentration-time profiles of MON and DA after oral administration of the MOIG at a dose of 25, 50 and 100 mg/kg and the MO extract of 1650 mg/kg in male rats (a and b), female rats (c and d) or intravenous administration of 25 mg/kg MOIG (e and f) in rats (n = 3, mean ± SD)

Fig. 4

The pie diagram of actual values of MON and DA in the MO (a) and MOIG (b). After oral administration of the 50 mg/kg MOIG and 1650 mg/kg MO extract, comparing the C_max (c) and absolute bioavailability (d) of MON and DA in female rats plasma