Pharmacokinetics and tissue distribution of liposomal etoposide in rats

Figures & data

Table 1.  Characterization of the liposomal formulations.

Formulation	Size (μm)^a	Encapsulation percentage	Percentage release^b
H:E	3.42 ± 0.05	72	49.09 ± 0.56
H:E:PG	3.07 ± 0.06	88	50.24 ± 0.63

Results shown are mean ± SE (n = 3).

^a Size, given as equivalent spherical diameter was determined using a Coulter counter as described in the text.

^b Percentage etoposide released from the liposomes after 4 h of incubation.

Figure 1.  Blood concentration-time profiles of etoposide after intravenous injection of 4.2 mg/kg etoposide to male Sprague-Dawley rats. Procedure detailed in Materials and Methods. Formulations administered were Etoposide Injection (ETPI, solid line), hydrogenated phosphatidyl choline: egg phosphatidyl choline (H:E; 4:6) without (broken line) and with phosphatidyl glycerate (H:E:PG; 4:6:1, dotted line). Data points represent mean ± SE (n ≥ 3). Line represents a two-compartmental fit to the data using WinNonlin, SCI Software.

Table 2.  Pharmacokinetic parameters after IV administration of etoposide to male Sprague-Dawley rats (dose 4.2 mg/kg).

Parameters	ETPI	H:E	H:E:PG
Cmax	4.4 ± 1.7	10.8 ± 7.1	4.5 ± 1.5
t1/2α (h)	0.11 ± 0.05	0.24 ± 0.14	0.13 ± 0.04
t1/2β (h)	1.00 ± 0.35	2.96 ± 0.47	2.30 ± 0.35
Cl (l/h)	0.71 ± 0.06	0.46 ± 0.06	0.45 ± 0.03
Vdss (l)	1.39 ± 0.52	1.05 ± 0.18	1.36 ± 0.18
AUC (mg/h/l)	1.74 ± 0.18	2.23 ± 0.36	3.33 ± 023
MRT (h)	1.71 ± 0.41	2.57 ± 0.73	3.19 ± 0.57

Results shown are mean ± SE (n ≥ 3).

t_1/2α: distribution half-life from 2-compartment model fitting; t1_/2β: elimination half-life from a non-compartmental fitting; Cl: total clearance from a non-compartmental fitting; Vd_ss: volume of distribution at steady state; AUC: area under the curve calculated using the trapeziodal rule and blood drug concentration time curve; MRT: mean residence time.

Table 3.  Micro-constants obtained from fitting data to a 2-compartment model following IV administration of etoposide to male Sprague-Dawley rats (dose 4.2 mg/kg).

Parameters	ETPI	H:E	H:E:PG
k12 (h^−1)	3.88 ± 1.95	4.52 ± 0.99	3.07 ± 0.75
k21 (h^−1)	3.81 ± 1.60	1.22 ± 0.54	0.47 ± 0.17
k10 (h^−1)	2.67 ± 1.16	4.62 ± 3.03	1.09 ± 0.68
Vc (l)	0.41 ± 0.11	0.25 ± 0.09	0.41 ± 0.09

Results shown are mean ± SE (n ≥ 3).

k₁₂: apparent rate constant for transport of drug from central compartment to the peripheral compartment obtained from 2-compartment model fitting; k₂₁: apparent rate constant for transport of drug from peripheral compartment to the central compartment obtained from 2-compartment model fitting; k₁₀: apparent elimination rate constant from the central compartment; Vc: volume of central compartment.

Figure 2.  Tissue distribution of etoposide, 3 h after intravenous administration of the formulations, in male Sprague-Dawley rats. Each bar with error bar depicts mean + SE.

Table 4.  Tissue distribution of etoposide following IV administration of the formulations to male Sprague-Dawley rats (dose 4.2 mg/kg).

Tissue	Time (h)	ETPI	H:E	H:E:PG
Blood (µg/mL)	0.5	0.40 ± 0.06	0.60 ± 0.20	0.60 ± 0.07
Lungs (µg/g)	0.5	29.71	NDp	94.01 ± 5.50
	3	0.38 ± 0.23	5.20 ± 0.59	20.73 ± 4.41
	6	0.65 ± 0.10	2.64 ± 1.45	5.41 ± 1.71
Liver (µg/g)	0.5	8.22	ND	14.87 ± 0.09
	3	2.00 ± 0.80	2.85 ± 1.62	3.42 ± 0.36
	6	1.49 ± 2.58	1.43 ± 0.03	1.81 ± 0.42
Spleen (µg/g)	0.5	20.22	ND	20.63 ± 2.43
	3	0.48 ± 0.48	5.36 ± 0.18	3.51 ± 0.53
	6	0.27 ± 0.27	1.98 ± 1.38	1.96 ± 0.09
Kidney (µg/g)	0.5	39.78	ND	12.96 ± 1.49
	3	1.81 ± 1.81	0.65 ± 0.23	0.65 ± 0.65
	6	nd	0.13 ± 0.13	nd

Results shown are mean ± SE (n = 3).

ND; not determined; nd; not detected.