TABLE 3.

Metabolism studies of UH alkaloids.

Study type	Model/Subject	Drug/Route	Outcome	References
Liver first pass	Male rats	Gouteng-Baitouweng (25 g/kg), Oral	GM was detected in portal vein plasma, but not in systemic plasma	Tian et al. (2018)
	Male rats	Tianma-Gouteng granule (2.5 and 5 g/kg), Oral	GM and acidic or reduced/demethylated metabolites of GM were detected in plasma	Zhang et al. (2019b)
In vitro metabolism	Rat and human liver microsomes	GM	GM was metabolized into at least 13 metabolites including hydroxylated, dehydrogenated, hydroxylated/dehydrogenated, demethylated, and hydrated forms	Kushida et al. (2015)
	Human liver microsomes and recombinant human CYPs, RAF method	GM	GM was metabolized by CYP3A4 (61.3%), CYP2C19 (23.5%), and CYP2D6 (15.2%)	Matsumoto et al. (2016)
	Rat liver S9 and microsomes, recombinant rat CYPs	GM	CYP1A1, CYP2C6, CYP2C11, CYP2D1, and CYP3A2 were involved in GM metabolism	Kushida et al. (2021)
	Rat liver microsomes	IRP	25 metabolites produced by oxidation, hydrolysis, reduction, demethylation, hydroxylation, and dehydrogenation	Wang et al. (2016a)
	Rat liver microsomes	RP and IRP	Hydroxylation at the A-ring was the major metabolic pathway for RP	Wang et al. (2017)
			Oxidation at the C-ring was the major metabolic pathway for IRP
	recombinant rat CYPs	ICX	CYP2C19 and CYP2D6 were involved in the production of 18,19-dehydrocorynoxinic acid, and CYP3A4 was involved in the production of 5-oxo ICX.	Zhao et al. (2016b)
	Rat liver microsomes, specific inhibitors	IRP	CYP1A1/2, CYP2C, and CYP2D, but not CYP3A, are involved in the 10- and 11-hydroxylation of IRP.	Wang et al. (2010a)
	Rat liver microsomes, specific inhibitors	RP	CYP1A1/2, CYP2C, and CYP2D, but not CYP3A, are involved in the 10- and 11-hydroxylation of RP	Wang et al. (2010b)
	Rat liver microsomes, specific inhibitors	HTI and HTE	CYP2C is involved in the 10- and 11-hydroxylation of HTI and THE	Nakazawa et al. (2006)
In vivo metabolism	Male rats	Tianma-Gouteng Yin granule (2.5 and 5 g/kg), Oral	GM and acidic or reduced/demethylated metabolites of GM were detected in plasma.	Zhang et al. (2019b)
			Corynoxeinic acid, isocorynoxeinic acid, rhynchophyllinic acid, isorhynchophyllinic acid, and hirsuteinic acid, and their 22-O-β-glucuronides were detected in plasma and bile, respectively
	Rats	CX (0.105 mM/kg), oral	10- and 11-Hydroxy CX have been isolated from urine and faces, and 10-hydroxy CX 10-O-β-D-glucuronide and 11-hydroxy CX 11-O-β-D-glucuronide were isolated from the bile	Wang et al. (2014b)
	Rats	ICX (40 mg/k), oral	10- and 11-Hydroxy ICX, 10-hydroxy ICX 10-O-β-D-glucuronide and 11-hydroxy ICX 11-O-β-D-glucuronide were isolated from the bile	Chen et al. (2014)
	Rats	ICX (40 mg/kg), oral	11-hydroxy ICX, 5-oxoisocorynoxeinic acid-22-O-β-D-glucuronide, 10-hydroxy ICX, 17-O-demethyl-16,17-dihydro-5-oxo ICX, 5-oxoisocorynoxeinic acid, 21-hydroxy-5-oxo ICX, oxireno[18, 19]-5-oxo ICX, 18,19-dehydrocorynoxinic acid, 18,19-dehydrocorynoxinic acid B, CX, ICX-N-oxide, and CX-N-oxide were detected in urine	Qi et al. (2015)
	Rats	ICX (40 mg/kg), oral	18, 33, and 18 metabolites produced by hydrolysis, oxidation, isomerization, demethylation, epoxidation, reduction, glucuronidation, hydroxylation, and N-oxidation were detected in plasma, urine, and bile, respectively	Zhao et al. (2016a)
	Rats	ICX (40 mg/kg), oral	8,19-dehydrocorynoxinic acid, 18,19-dehydrocorynoxinic acid B, 5-oxoisocorynoxeinic acid-22-O-glucuronide, 17-O-demethyl-16,17-dihydro-5-oxo ICX, 5-oxoisocorynoxeinic acid, and 5-oxoisorhynchophyllic acid were identified in plasma	Zhao et al. (2016b)
	Rats	IRP (20 mg/kg), oral	10- and 11-Hydroxy IRP were isolated from urine and feces.	Wang et al. (2010a)
			10- and 11-Hydroxy IRP-β-O-glucuronides were isolated from bile
	Rats	RP (37.5 mg/kg), oral	10- and 11-Hydroxy RP were isolated from urine and feces.	Wang et al. (2010b)
			10- and 11-Hydroxy RP-β-O-glucuronides were isolated from bile
	Rats	IRP (20 mg/kg), oral	47, 21, and 18 metabolites of IRP were identified in rat urine, plasma, and liver, respectively	Wang et al. (2016a)
	Rats	HTI (20 mg/kg), oral	67 metabolites by hydroxylation, dehydrogenation, oxidation, N-oxidation, hydrolysis, reduction, and glucuronide conjugation	Wang et al. (2016b)
	Rats	HTI and HTE (50 mg/kg), oral	11-hydroxy HTE-11-O-β-D-glucuronide, 11-hydroxy HTE, 11-hydroxy HTI-11-O-β-D-glucuronide, and 11-hydroxy HTI from the bile and urine	Nakazawa et al. (2006)