Correlation between radioactivity and chemotherapeutics of the ¹¹¹In-VNB-liposome in pharmacokinetics and biodistribution in rats

Figures & data

Table 1 Intraday and interday assay for accuracy and precision for determination of vinorelbine

Intraday				Interday
Cnom (ng/mL)	Cobs (ng/mL)	RSD (%)a	Bias (%)b	Cnom (ng/mL)	Cobs (ng/mL)	RSD (%)a	Bias (%)b
Plasma
5	5.0 ± 0.6	12.0	0.0	5	5.8 ± 0.6	10.3	16.0
10	10.0 ± 0.2	2.0	0.0	10	10.9 ± 0.8	7.3	9.0
20	20.6 ± 0.2	1.0	3.0	20	21.2 ± 1.5	7.1	6.0
50	49.9 ± 1.3	2.6	−0.2	50	48.8 ± 0.0	0.0	−2.4
100	100.1 ± 0.7	0.7	0.1	100	97.9 ± 0.4	0.4	−2.1
200	199.8 ± 1.8	0.9	−0.1	200	196.7 ± 3.3	1.7	−1.7
500	500.7 ± 2.5	0.5	0.1	500	498.1 ± 5.1	1.0	−0.4
Liver
5	5.2 ± 0.7	13.5	4.0	5	5.4 ± 0.1	1.9	8.0
10	10.2 ± 1.0	9.8	2.0	10	9.0 ± 0.8	8.9	−10.0
20	20.2 ± 1.0	5.0	1.0	20	20.8 ± 1.7	8.2	4.0
50	50.5 ± 0.4	0.8	1.0	50	48.0 ± 2.9	1.9	−4.0
100	99.9 ± 1.5	1.5	−0.1	100	101.1 ± 1.4	1.4	1.1
200	198.4 ± 2.2	1.1	−0.8	200	201.7 ± 2.7	1.3	0.8
500	500.6 ± 0.9	0.2	0.1	500	499.8 ± 0.6	0.1	0.0
Spleen
5	5.8 ± 0.2	3.4	16.0	5	4.8 ± 0.6	12.5	−4.0
10	9.9 ± 0.6	6.1	−1.0	10	10.0 ± 0.5	5.0	0.0
20	19.3 ± 1.5	7.8	−3.5	20	19.1 ± 0.5	2.6	−4.5
50	50.7 ± 3.3	6.5	1.4	50	50.2 ± 1.0	2.0	0.4
100	101.4 ± 3.0	3.0	1.4	100	101.7 ± 6.9	6.8	1.7
200	197.3 ± 5.3	2.7	−1.3	200	199.4 ± 7.3	3.7	−0.3
500	501.1 ± 3.1	0.6	0.2	500	500.2 ± 3.4	0.7	0.0

Notes: Data are expressed as mean ± standard deviation (n = 3).

a RSD (%) = [standard deviation/C_obs] × 100;

b bias (%) = [(C_obs − C_nom)/C_nom] × 100.

Abbreviation: RSD, relative standard deviation.

Table 2 Matrix effect and recovery for the determination of vinorelbine

Concentration (ng/mL)	Matrix effect (%)	Recovery (%)
Plasma
5	99.3 ± 13.7	95.3 ± 19.5
50	102.1 ± 7.2	103.9 ± 6.8
500	82.0 ± 4.6	90.9 ± 6.4
Average	94.4 ± 10.9	96.7 ± 6.6
Liver
5	102.0 ± 2.2	85.4 ± 8.2
50	95.4 ± 3.4	84.3 ± 2.4
500	88.0 ± 2.6	79.2 ± 3.2
Average	95.2 ± 7.0	82.9 ± 3.3
Spleen
5	93.0 ± 5.3	69.0 ± 2.6
50	97.2 ± 2.8	72.4 ± 2.0
500	94.5 ± 4.4	80.0 ± 3.7
Average	94.9 ± 2.1	73.8 ± 5.6

Notes: Data are expressed as mean ± standard deviation (n = 3). Set 1 = neat sample (vinorelbine prepared in normal saline); set 2 = postextraction fortification; set 3 = pre-extraction fortification; matrix effect (%) = (mean area of set 2/mean area of set 1) × 100; Recovery (%) = (mean area of set 3/mean area of set 2) × 100.

Figure 1 Typical liquid chromatography tandem mass spectrometry images of vinorelbine. (A) Blank plasma sample, (B) blank plasma spiked vinorelbine sample (200 ng/mL), (C) real plasma sample (156 ng/mL, t = 24 hours), (D) blank liver sample, (E) blank liver spiked vinorelbine sample (200 ng/mL), (F) real liver sample (141 ng/mL, t = 4 hours), (G) blank spleen sample, (H) blank spleen spiked vinorelbine sample (500 ng/mL), (I) real spleen sample (424 ng/mL, t = 1 hour).

Note: The maximal signal intensities for plasma, liver and spleen samples were 9.0 × e5, 1.3 × e6, and 8.5 × e5, respectively.

Table 3 Pharmacokinetic parameters of vinorelbine in plasma of rats administered with VNB-liposome (0.3 mg/kg VNB) and ¹¹¹In-VNB-liposome (0.3 mg/kg vinorelbine, 2.22 MBq/rat)

	VNB-liposome	^111In-VNB-liposome
Blood
t1/2 (hours)	4.8 ± 1.2	3.3 ± 1.3
C0 (μg/mL)	6.27 ± 2.68	7.15 ± 1.60
AUC0–24 h (h * μg/mL)	65.5 ± 26.6	44.5 ± 31.0
Liver
Cmax (μg/g)	0.35	0.19
AUC0–24 h (h * μg/g)	5.26	3.54
Spleen
Cmax (μg/g)	2.47	2.86
AUC0–24 h (h * μg/g)	47.0	57.5

Notes: Data are expressed as the mean ± standard deviation. Pharmacokinetic parameters: t_1/2, half life; C₀, extrapolated blood concentration at time 0; AUC_{0–24 h}, area under concentration–time curve; C_max, maximum drug concentration. Blood sample: n = 5; liver and spleen: n = 3 for each sampling time (1, 4, and 24 hours). Mean concentrations at 1, 4, and 24 hours constructed the time-concentration profile of liver and spleen to obtain C_max and AUC_{0–24 h}.

Abbreviation: VNB, vinorelbine.

Figure 2 Vinorelbine concentration-time curve and radioactivity-time curve in plasma. ◆ Vinorelbine concentration of the VNB-liposome (vinorelbine 0.3 mg/kg) intravenous administration group, ■ vinorelbine concentration of ¹¹¹In-VNB-liposome (vinorelbine 0.3 mg/kg, Indium-111 2.22 MBq/rat) intravenous administration group, and ▴ radioactivity of of ¹¹¹In-VNB-liposome (vinorelbine 0.3 mg/kg, Indium-111 2.22 MBq/rat) intravenous administration group.

Note: Data are expressed as the mean ± standard error of the mean (n = 5 for each group).

Abbreviation: VNB, vinorelbine.

Figure 3 VNB concentration-time curve and radioactivity-time curve in liver and spleen. ◆ Vinorelbine concentration of liver in the group of VNB-liposome (vinorelbine 0.3 mg/kg) intravenous administration; ⋄ Vinorelbine concentration of spleen in the group of VNB-liposome (vinorelbine 0.3 mg/kg) intravenous administration; ■ vinorelbine concentration of liver in the group of ¹¹¹In-VNB-liposome (vinorelbine 0.3 mg/kg, 2.22 MBq/rat) intravenous administration; □ vinorelbine concentration of spleen in the group of ¹¹¹In-VNB-liposome (vinorelbine 0.3 mg/kg, 2.22 MBq/rat) intravenous administration; • radioactivity of liver in the group of ¹¹¹In-VNB-liposome (vinorelbine 0.3 mg/kg, 2.22 MBq/rat) intravenous administration; ○ radioactivity of spleen in the group of ¹¹¹In-VNB-liposome (vinorelbine 0.3 mg/kg, 2.22 MBq/rat) intravenous administration.

Note: Data are expressed as mean ± standard error of the mean (n = 3 for each time point per group).

Abbreviation: VNB, vinorelbine.

Figure 4 Correlation of pharmacokinetics between radiolabeled tracer and vinorelbine concentration in ¹¹¹In-VNB-liposome (vinorelbine 0.3 mg/kg, 2.22 MBq/rat) post intravenous administration.

Note: Data are expressed as mean ± standard error of the mean (n = 5 for each time point per group).

Abbreviation: VNB, vinorelbine.