UPLC-MS/MS Measurement of the Effect of Isavuconazole, Itraconazole and Fluconazole on the Pharmacokinetics of Selinexor in Rats

Figures & data

Figure 1 The chemical structure of selinexor (A) and pirfenidone (IS, (B)).

Figure 2 Continued.

Figure 2 Representative chromatograms in positive ion mode. (A) A blank plasma sample; (B) a blank plasma sample spiked with selinexor and IS; (C) a rat plasma sample three hours after oral administration of selinexor (8 mg/kg).

Table 1 Regression Equation, Linearity Range, Correlation Coefficients and LLOQ of Selinexor

Analytes	Regression Equation	Linearity Range (ng/mL)	R^2	LLOQ (ng/mL)
Selinexor	y = 0.5469*x + 0.4651	1, 5, 10, 50, 100, 200, 500, 1000	0.999 4	1

Table 2 Precision and Accuracy of Selinexor in Rat Plasma (n=6)

Spiked (ng/mL)	Intraday			Interday
	Mean ±SD	RSD (%)	RE (%)	Mean ±SD	RSD (%)	RE (%)
1	0.98±0.06	6.5	−2.3	0.98±0.05	5.1	−2.2
2.5	2.51±0.08	3.3	0.2	2.47±0.09	3.8	−1.3
200	204.88±10.11	4.9	2.4	196.20±9.30	4.7	−1.9
800	809.47±32.58	4.0	1.2	790.39±30.59	3.9	−1.2

Table 3 The Recoveries and ME of Selinexor and is in Rat Plasma (n=6, Mean ±SD)

Compounds	Spiked (ng/mL)	Recoveries (%)	ME (%)
Selinexor	2.5	91.10±4.24	106.24±7.35
	200	87.60±4.25	102.15±5.75
	800	85.71±4.71	98.67±3.96
IS	10	85.39±5.73	96.76±5.84

Table 4 The Stability of Selinexor and is in Rat Plasma (n=6)

Spiked (ng/mL)	Room Temperature, 4 h		Autosampler 4°C, 24 h		Three Freeze–thaw		−20°C, Four Weeks
	RSD (%)	RE (%)	RSD (%)	RE (%)	RSD (%)	RE (%)	RSD (%)	RE (%)
2.5	6.0	−2.6	5.4	4.5	4.9	5.4	4.2	5.1
200	4.2	1.7	3.9	1.8	4.2	1.8	4.2	−3.3
800	4.1	0.3	5.0	2.3	4.2	2.8	4.2	3.0

Table 5 The Stock Solution Stability of Selinexor and is in Rat Plasma (n=6)

Compounds	Spiked (μg/mL)	Room Temperature, 12 h		−20°C, Three Weeks
		RSD (%)	RE (%)	RSD (%)	RE (%)
Selinexor	10	3.6	−1.6	3.6	3.2
IS	10	7.8	−0.4	6.3	2.1

Table 6 Pharmacokinetic Parameters of Selinexor After Oral Administration to 8 mg/kg Selinexor (n=6, Mean ±SD)

Parameters	Group A	Group B	Group C	Group D
t1/2 (h)	6.35±1.09	5.33±0.97	5.71±0.36	7.73±3.41
Tmax (h)	0.97±0.37	1.53±0.58**	1.58±0.38**	1.67±0.26**
MRT(0–t) (h)	10.06±3.01	7.40±0.98	8.43±0.73	8.61±1.49
MRT(0–∞) (h)	10.32±3.04	7.58±1.03	8.57±0.74	8.65±1.30
Cmax (ng/mL)	575.81±249.37	915.81±184.19**	899.06±118.99**	825.92±121.84**
CLz/F (L/h/kg)	1.74 ±0.44	1.29±0.22*	1.36±0.24*	1.35±0.39*
AUC(0-t) (ng·h/mL)	4815.84±1219.40	6342.19±1121.89*	6036.04±1006.55*	6220.17±1663.77*
AUC(0-∞) (ng·h/mL)	4839.47±1227.03	6361.33±1137.68*	6052.99±1009.75*	6386.17±1910.92*

Note: (Compared with the Group A, *P<0.05; **P<0.01).

Abbreviations: t_1/2, half-life; T_max, time of peak concentration; MRT_(0-t), mean residence time of 0-t time; MRT_(0–∞), mean residence time of 0-infinity time; C_max, peak concentration; AUC_(0-t), area under curve of 0-t time; AUC_(0-∞), area under curve of 0-infinity time.

Figure 3 The mean plasma concentration-time curve of selinexor (zoomed one to six hours pharmacokinetic profile). Group A, normal saline; Group B, isavuconazole (20 mg/kg); Group C, itraconazole (20 mg/kg); and Group D, fluconazole (20 mg/kg) (n=6).