TABLE 2.

Pharmacokinetic parameters of prodrugs 12, 14, 17, and 18

Drug and routea	Parameterb	Value for the prodrugc
		12	14	17	18
Intact prodrug in plasma
i.v.	Vss (l/kg)	0.4	ND	0.5	0.5
	ER (%)	>100		67	45
	t1/2 (h)	0.1		0.3	0.3
p.o.	Cmax (μM)	1.0	0.8	2.5	1.8
	Tmax (h)	0.08	0.25	0.08	0.25
	AUClast (μM⋅h)	0.3	0.5	1.6	1.3
	F (%)	25	ND	44	24
Nucleoside metabolite 7 in plasma
i.v.	t1/2 (h)	4.0	4.0	3.4	3.9
p.o.	Cmax (μM)	0.8	0.8	0.5	1.3
	Tmax (h)	0.5	0.5	2	1
	AUC0–24 (μM⋅h)	4.1	2.4	4.5	6.8
Triphosphate metabolite 6 in PBMCs
p.o.	Cmax	0.7	0.9	2.7	0.7
	Tmax	1.0	16	11	4.7
	AUC0–24	8.5	13.0	43.5	12.3

^aBeagle dogs (n = 3) were dosed i.v. at 0.5 mg/kg and p.o. at 3 mg/kg.

^bV_ss, volume of distribution at steady state; ER, hepatic extraction ratio, calculated from the i.v. clearance using a dog liver blood flow of 42 ml/min/kg; t_1/2, elimination half-life; C_max, maximum concentration; T_max, time to reach maximum concentration; AUC_last, area under the concentration-time curve (from t = 0 until the last measurable concentration); AUC_0–24, area under the concentration-time curve for t = 0 to 24 h; F, bioavailability.

^cND, not determined.