Comparative Assessment of Distribution Characteristics and Ocular Pharmacokinetics of Norvancomycin Between Continuous Topical Ocular Instillation and Hourly Administration of Eye Drop

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Figure 1 Illustration of the CTOIDD system model (A); the tube section was fixed on the conjunctiva of a rabbit eye (B, C); the pump section was connected with the tube and delivered the norvancomycin to the ocular surface. Rabbits were kept in individual cages with food and water provided during drug administration (D).

Abbreviations: NVCM, norvancomycin; CTOIDD, continuous topical ocular drug delivery.

Figure 2 Structural formula of (A) norvancomycin; (B) vancomycin.

Figure 3 Chromatograph of blank plasma in the HPLC-PDA method (A); chromatograph of blank plasma spiked with norvancomycin and vancomycin (B).

Abbreviation: HPLC-PDA, high-performance liquid chromatography with photodiode array detector.

Table 1 Mean Recovery Rates of Norvancomycin and Vancomycin in Plasma

Drug	Added (μg/mL)	Recovery (%)	RSD (%) (n=5)
Norvancomycin	3.12	75.6	4.5
	12.5	76.2	5.2
	50.0	75.9	4.9
Vancomycin	60.0	76.1	5.0

Abbreviation: RSD, relative standard deviation.

Table 2 Intra-Day Precision and Inter-Day Precision

Concentration (μg/mL)	Intra-Day		Inter-Day
	Mean Observed Concentration (n=5)	RSD (%)	Mean Observed Concentration (n=5)	RSD (%)
3.12	3.20	6.7	3.16	6.3
12.5	12.4	1.2	12.6	2.1
50.0	50.1	1.5	49.9	1.9

Abbreviation: RSD, relative standard deviation.

Table 3 Stability of Long-Term Storage

Time	Concentration (μg/mL)	Mean Observed Concentration (n=5)	RSD (%)
5 days	3.12	3.18	6.2
	12.5	12.3	1.5
	50.0	50.2	1.6
30 days	3.12	3.09	5.9
	12.5	12.4	1.7
	50.0	50.1	2.2

Abbreviation: RSD, relative standard deviation.

Table 4 Norvancomycin Concentrations in the Anterior Segment Tissue and Blood Plasma in OTCIDD and Eye Drop Groups

Hours (h)	Eye Drop Group (μg/g, μg/mL)	OTCIDD Group (μg/g, μg/mL)
Conjunctiva
2	179.00±53.62	1330.01±793.57*
4	806.99±563.02	2221.90±1262.92
6	240.47±114.40	3033.92±1061.95**
10	145.16±34.96	1821.14±853.74**
24	51.57±13.47 (F=36.369)	249.70±62.11** (p<0.01)
Cornea
2	68.04±51.15	1317.67±558.19**
4	97.18±43.14	1903.32±814.24**
6	66.36±54.87	2105.45±919.89**
10	43.53±21.15	1522.79±778.26**
24	15.85±6.51 (F=64.744)	243.77±73.00** (p<0.01)
Iris
2	46.93±23.46	293.41±558.19*
4	39.98±8.75	1570.19±402.87**
6	44.75±18.32	651.39±259.50**
10	41.95±13.24	318.09±147.07**
24	12.58±4.03 (F=25.600)	56.08±23.45** (p<0.01)
Ciliary Body
2	17.75±12.96	90.75±41.86**
4	10.73±6.35	181.94±47.11**
6	15.38±4.00	148.09±28.52**
10	11.38±6.52	101.81±33.77**
24	6.67±4.29	24.60±10.23*
	(F=69.361)	(p<0.01)
Aqueous Humour
2	0.95±0.75	2.72±1.05
4	1.18±0.24	6.17±4.39*
6	3.20±1.48	15.73±4.51**
10	1.39±0.39	29.78±4.90**
24	0.90±0.44 (F=30.949)	6.93±2.45** (p<0.01)
Blood Plasma
2	1.90±1.87	6.11±4.23
4	1.18±1.20	9.05±5.05*
6	1.58±1.047	26.89±5.57**
10	1.46±0.44	16.59±4.26**
24	0.57±0.250 (F=33.948)	1.30±0.72 (p<0.01)

Notes: *p<0.05, **p<0.01.

Figure 4 Concentration–time curve of norvancomycin concentration in conjunctiva (A), cornea (B), iris (C), ciliary body (D), aqueous humour (E), and blood plasma (F) in the two groups. The aread under the concentration–time curve from 0 to 24 h were compared using the t-test. Values are given as the mean±SD (n=6), **p<0.01.

Figure 5 Comparison of the levels of norvancomycin at different time-points between the two groups in conjunctiva (A), cornea (B), iris (C), ciliary body (D), aqueous humour (E), and blood plasma (F). One-way analysis of variance was used to compare the overall difference between the CTOIDD group and eye drop group. Values are given as the mean±SD (n=6), *p<0.05, **p<0.01.

Table 5 Concentration Ratio of Conjunctiva/Cornea, Iris/Cornea, and Plasma/Cornea in OTCIDD and Eye Drop Groups

Hour	2	4	6	10	24
OTCIDD group
Conjunctiva/cornea	1.009	1.167	1.441	1.196	1.024
Iris/cornea	0.222	0.825	0.309	0.209	0.230
Plasma/cornea	0.005	0.005	0.013	0.011	0.005
Eye drop group
Conjunctiva/cornea	2.631	8.304	3.624	3.334	3.253
Iris/cornea	0.690	0.411	0.674	0.964	0.794
Plasma/cornea	0.028	0.012	0.024	0.034	0.036

Figure 6 Norvancomycin concentration–time profiles in different anterior segment tissue and blood plasma in the CTOIDD group (A) and eye drop group (B).

Table 6 Pharmacokinetic Parameters of Norvancomycin in Rabbit’ Anterior Segment Tissue in OTCIDD and Eye Drop Groups

	Conjunctiva	Cornea	Iris	Ciliary Body	Aqueous Humour	Blood Plasma
OTCIDD group
Cmax (μg/g), (μg/mL)	3033.92	2105.45	1570.19	181.94	29.78	26.89
Tmax (h)	6	6	4	4	10	6
AUC0–24 (μg·h/g), (μg·h/mL)  T1/2 (h)	32,514.48 4.97	27,543.70 5.65	8631.05 5.21	2194.36 6.93	343.94 6.66	234.36 4.03
Eye drop group
Cmax (μg/g), (μg/mL)	806.99	97.18	46.93	17.75	3.2	1.9
Tmax (h)	4	4	2	2	6	2
AUC0–24 (μg·h/g), (μg·h/mL)  T1/2 (h)	4505.89 8.40	1075.80 8.93	813.68 9.30	252.16 15.65	31.92 11.51	29.22 11.59

Abbreviations: Cmax, peak concentration; Tmax, time to peak concentration; AUC_0–24, area under the concentration-time curve between 0 and 24 h.