In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1

Figures & data

Figure 1. The structure of Inh 1 (1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxy-phenyl)-1-(2-hydroxy-ethyl)thiourea).

Figure 2. Upper: Summed XIC of all the metabolites of Inh 1 found in 120 min human hepatocyte samples, Middle: Summed XIC of all the metabolites found in 20 min mouse hepatocyte samples Lower: Summed XIC of all the metabolites found in 20 min rat hepatocyte samples Unfilled peaks are considered to arise from endogenous material.

Figure 3. Proposed structures for hepatocyte-derived metabolites of Inh 1

Table 1. Pharmacokinetic parameters for Inh 1 following IV and PO Administration to Swiss Mice at 3 mg/kg.

Compound	Route	Tmax (hr)	Cmax^a(ng/mL)	AUClast (hr*ng/mL)	AUCINF (hr*ng/mL)	T1/2 (hr)	CL (mL/min/kg)	Vss (L/kg)	Fb (%)
Inh 1	IV	–	3872	3518	3518	0.91	14.2	0.63	–
	PO	0.5	495	904	928	–	–	–	25.7

^a C_o for iv; based on simple (perpendicular) back extrapolation of the Inh 1 concentration at 0.08 h.

^b AUC_last considered for bioavailability calculation.

Figure 4. The oxidative desulfurization of 6-(2,4-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one by FMO by rat and dog microsomes. Adapted from Eng et al. (2016).

Figure 5. Proposed biotransformations leading to metabolites showing desaturation -H2S.

Figure 6. Mean plasma concentration-time profiles to 8 h for Inh 1 following single intravenous and oral administration to Swiss albino mice both at 3 mg/kg. Key: -

-, IV; - O - PO.

Eng H, Sharma R, Wolford A, Li D, Ruggeri RB, Buckbinder L, Conn EL, Dalvie DK, Kalgutkar AS. 2016. Species differences in the oxidative desulfurization of a thiouracil-based irreversible myeloperoxidase inactivator by flavin-containing monooxygenase enzymes. Drug Metab Dispos. 44:1262–1269.

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.