An Investigation on Liver-Targeting Microemulsions of Norcantharidin

Figures & data

FIG. 1. Transmission electron microscopy photographs (× 20000) of NCTD-loaded microemulsion following negative staining with dilution factor of 1000×.

FIG. 2. In vitro release of NCTD from microemulsion to PBS (pH = 7.4) at 37°C as a function of time. Each point represents the mean of three determinations.

TABLE 1 Comparison of the blood pharmacokinetic parameters in mice between NCTD injection and NCTD-loaded microemulsion (mean) (n = 5, x ± s)

Parameter	Injection	Microemulsion
A mg/L	4.4 ± 1.1	1.8 ± 1.0
α h^− 1	5.7 ± 1.2	1.5 ± 0.8
B mg/L	0.2 ± 0.1	0.16 ± 0.1
β h^− 1	0.1 ± 0.02	6.7 × 10^− 3
Vc L	0.11 ± 0.02	0.01 ± 0.001
T1/2α h	0.27 ± 0.07	0.45 ± 0.08
T1/2β h	41.77 ± 4.23	103.3 ± 12.4
K21 h^− 1	0.15 ± 0.06	0.13 ± 0.07
K12 h^− 1	2.60 ± 1.0	2.32 ± 0.8
K10 h^− 1	0.36 ± 0.15	0.08 ± 0.01
AUC mg· h·L^− 1	9.25 ± 0.09	29.68 ± 0.86
CL L· h^− 1	0.03 ± 0.001	0.001 ± 0.001
MRT h	86.68 ± 0.8	109.80 ± 11.23

*p ≤ 0.05; the data were mean ±S.D. (n = 5). [A and B = the hybrid parameter, α = distribution constant, β = elimination constant, Vc = apparent volume of distribution of the center compartment, T_1/2α = half-time of phase I; T_1/2β = half-time of phase II; K₂₁ = rate constant for drug leaving from compartment 2 to 1, K₁₂ = rate constant for drug leaving from compartment 1 to 2, K₁₀ = elimination constant of the center compartment, AUC = area under curve; CL = clearance from the two-compartment model, MRT h = mean retention time.

FIG. 3. Percentage of total administration dosage of NCTD-loaded microemulsion (ME) and NCTD injection in mice liver (a), kidney (b) following i.v. administration (5 mg/kg, NCTD).

TABLE 2 Major pharmacokinetic parameters for NCTD-loaded microemulsion in mice

Tissue	AUC0.∞ (μg·h/g)	Tmax (hr)	Cmax (μg/g)	t1/2 (hr)	MRT0 .∞ (hr)
Heart	232.93	1	2.20	95.77	139.4
Liver	14181.23	0.5	63.78	220.77	176.20
Spleen	488.08	0.08	4.14	124.14	158.30
Lung	191.73	0.08	1.84	89.14	145.13
Kidney	505.85	4	4.77	88.75	148.29

TABLE 3 Major pharmacokinetic parameters for NCTD injection in mice

Tissue	AUC0.∞ (μg·h/g)	Tmax (hr)	Cmax (μg/g)	t1/2 (hr)	MRT0.∞ (hr)
Heart	214.80	3	1.87	122.72	160.58
Liver	3998.11	2	61.91	78.68	98.14
Spleen	335.83	3	3.35	112.68	142.15
Lung	235.01	3	3.51	158.54	134.77
Kidney	304.65	4	18.09	175.43	193.48

TABLE 4 AUC and tissue uptake clearances of NCTD injection and NCTD-loaded microemulsion after administration

	Blood		Tissue uptake clearance (ml/h·g)
Drugs	t (hr)	(μg* h/ml)	Heart	Liver	Spleen	Lung	Kidney
NCTD Injection	0.5	0.5	2.5	35.7	2.2	1.1	8.2
	3.0	5.2	0.4	7.4	0.4	0.5	4.4
NCTD-loaded Microemulsion	0.5	2.1	1.8	28.4	1.3	0.4	3.3
	3.0	18.6	0.1	2.0	0.1	0.06	0.3

AUC and tissue uptake clearances were calculated for the initial phase until 0.5 and 3 hr after intravenous administration.

TABLE 5 Overall targeting efficiency of NCTD-loaded microemulsion and NCTD injection (n = 5, x = ± s, %)

Tissue	Liver	Heart	Spleen	Lung	Kidney	Blood
NCTD-loaded Mcroemulsion	6.10 ± 0.15	0.01 ± 0.02	0.03 ± 0.03	0.01 ± 0.02	0.03 ± 0.01	1.8 × 10^−3
NCTD injection	3.66 ± 0.14	0.04 ± 0.07	0.07 ± 0.02	0.05 ± 0.07	0.06 ± 0.05	5.5 × 10^−4

TABLE 6 Targeting evaluation of NCTD-loaded microemulsion compared with NCTD injection

Tissue	Liver	Heart	Spleen	Lung	Kidney	Blood
Re	3.55	1.08	1.45	0.82	1.66	4.07
RTe (%)	0.67	−0.75	−0.57	−0.80	−0.50	1.95

Re = the targeting index, R_Te = the relative overall targeting efficiency.