Determination and pharmacokinetic study of isothiouronium-modified pyrimidine-substituted curcumin analog (1G), a novel antitumor agent, in rat plasma by liquid chromatography–tandem mass spectrometry

Figures & data

Figure 1. Chemical structure of curcumin.

Figure 2. Chemical structures of 1G (A) and IS (B).

Figure 3. Product ion mass spectrum of 1G (A) and IS (B).

Figure 4. Representative MRM chromatograms of 1G (1) and IS (2) in rat plasma samples: (A) blank plasma sample; (B) blank plasma sample spiked with 1G (5 ng/mL, LLOQ) and IS (100 ng/mL); and (C) plasma sample at 10 min after an intravenous administration of 5 mg/kg 1G.

Table 1. Intra- and inter-day precision and accuracy of the method for 1G in rat plasma (n = 5).

	Spiked concentration (ng/mL)	Measured concentration (mean ± SD, ng/mL)	Accuracy (RE, %)	Precision (RSD, %)
Intra-day	10	10.81 ± 0.79	8.1	7.3
	100	105.36 ± 9.56	5.4	9.1
	500	504.73 ± 38.53	0.9	7.6
Inter-day	10	10.33 ± 1.04	3.3	10.1
	100	102.62 ± 8.75	2.6	8.5
	500	500.56 ± 34.19	0.1	6.8

Table 2. Recovery and matrix effect of the method for 1G and IS in rat plasma (n = 5).

Compd.	Spiked concentration (ng/mL)	Recovery		Matrix effect
		Mean ± SD (%)	RSD (%)	Mean ± SD (%)	RSD (%)
1G	10	100.8 ± 5.4	5.4	93.9 ± 4.3	4.6
	100	95.3 ± 4.6	4.9	94.3 ± 2.1	2.2
	500	98.3 ± 4.4	4.5	96.1 ± 2.6	2.7
IS	100	101.1 ± 2.7	2.7	96.6 ± 1.7	1.8

Table 3. Stability of the method for 1G in rat plasma (n = 5).

Spiked concentration (ng/mL)	Condition	Measured concentration (mean ± SD, ng/mL)	RSD (%)	RE (%)
10	Control	10.38 ± 1.37	13.2	3.8
	6 h at 25 °C	9.24 ± 0.51	5.5	−7.6
	4 weeks at −20 °C	10.47 ± 0.99	9.5	4.7
	Three freeze-thaw cycles	9.83 ± 0.52	5.3	−1.7
	Autosampler for 24 h	9.38 ± 0.58	6.2	−6.2
100	Control	105.36 ± 9.56	9.1	5.4
	6 h at 25 °C	101.61 ± 4.06	4	1.6
	4 weeks at −20 °C	110.86 ± 2.85	2.6	10.9
	Three freeze-thaw cycles	95.17 ± 5.92	6.2	−4.8
	Autosampler for 24 h	109.00 ± 6.67	6.1	9.0
500	Control	504.73 ± 38.53	7.6	0.9
	6 h at 25 °C	477.16 ± 28.30	5.9	−4.6
	4 weeks at -20 °C	514.17 ± 50.76	9.9	2.8
	Three freeze-thaw cycles	496.68 ± 56.52	11.4	−0.7
	Autosampler for 24 h	466.52 ± 40.31	8.6	−6.7

Figure 5. Mean concentration–time curves of 1G following single-dose intravenous administration (A) and intraperitoneal injection (B) at 5 mg/kg in rats (mean ± SD, n = 6).

Table 4. Pharmacokinetic parameters of 1G following single-dose intravenous administration and intraperitoneal injection at 5 mg/kg in rats (n = 6).

Parameters	Unit	Intravenous		Intraperitoneal
		Mean	SD	Mean	SD
AUC(0–t)	μg/L·h	515.08	169.39	322.33	49.16
AUC(0–∞)	μg/L·h	553.30	170.35	353.63	59.29
MRT(0–t)	H	2.72	0.43	4.36	0.25
MRT(0–∞)	H	3.94	0.64	5.45	1.03
t1/2	H	4.06	1.61	3.03	1.06
Tmax	H	0.08	0.00	2.17	0.41
Vz	L/kg	62.91	44.09	61.87	19.35
CLz	L/h/kg	9.92	3.59	14.48	2.46
Cmax	μg/L	402.17	85.37	57.61	10.59
F	%	100.00	–	62.58	–

AUC_(0–t): area under the curve from time zero to the last sampling time point; AUC_(0–∞): area under the curve from time zero to the infinity; MRT_(0–t): mean residence time from time zero to the last sampling time point; MRT_(0–∞): mean residence time from time zero to the infinity; t_1/2, elimination half-life; T_max, time of maximum concentration; V_z: apparent volume of distribution; CL_z: clearance; C_max: maximum concentration; F: bioavailability.