TABLE 1.

Values of pharmacokinetic parameters of D-D4FC derived from monkeys given 33.3 mg/kg by i.v. or p.o. route

Route and model parametera	Mean (n = 3)	Minimum	Maximum	Fit to averaged data
i.v. route
t1/2α (h)	0.69	0.61	0.83	0.77
t1/2β (h)	3.57	3.46	3.75	3.26
% AUC from α phase	53.5	46.3	57.8	53.2
% AUC from β phase	46.5	42.2	53.7	46.8
k10 (h−1)	0.63	0.57	0.69	0.58
k12 (h−1)	0.27	0.17	0.34	0.20
k21 (h−1)	0.31	0.29	0.36	0.33
Vcentral (liter · kg−1)	0.68	0.58	0.79	0.70
VSS (liter · kg−1)	1.24	1.16	1.32	1.13
CLsys (liter · kg−1 · h−1)	0.43	0.40	0.45	0.40
AUC (μM · h)	345.5	327.4	363.9	363.5
AUMC (μM · h−2)	1,014.1	917.1	1,075.7	1,017.3
MRTi.v. (h)	2.93	2.80	3.12	2.80
r (n)	0.973 (10)	0.937 (10)	0.994 (10)	0.970
CLR (liter · kg−1 · h−1)	0.31	0.27	0.35
p.o. route
ka (h−1)	0.64	0.50	0.86	0.26
tlag (h)	0.88	0.00	1.83	0.00
F	0.41	0.24	0.49	0.41
r	0.94	0.90	0.99	0.90
Cmax (μM)	33.4	21.1	47.5
Tmax	2.67	1.00	4.00
AUC (μM · h)	172.0	104.6	211.7
AUMC (μM · h2)	1,029.8	669.7	1,242.1
MRT p.o. (h)	6.06	5.56	6.40
MAT (h)	3.13	2.68	3.42

^aThe values of the model parameters were determined by simultaneously fitting the data for plasma following administration by the i.v. and oral routes to a two-compartment model. The model parameters included t_1/2α and t_1/2β, the respective disposition half-lives; k₁₀ is the elimination rate constant from the central compartment; k₁₂ and k₂₁ are the disposition rate constants between the central and peripheral compartment; V_central is the distribution volume of the central compartment; V_SS is the distribution volume once the compound has distributed throughout animal; CL_R and CL_sys are the renal and systemic clearances, respectively; C_max is the observed maximum concentration in plasma, while T_max is the time to C_max. F is the fraction of the oral dose of compound absorbed. CL_R was calculated for the i.v. dose as the ratio of compound recovered in the urine/AUC. AUC and AUMC values are the area under zero and first moment plasma concentration-versus-time curves, respectively; MRT is the mean residence time; r is the correlation coefficient, and n is the number of observation points. k_a is the first-order oral absorption rate constant. The mean absorption time (MAT) was calculated as the difference between each animal’s own MRT after p.o. administration and the corresponding MRT after i.v. administration (4). CL_R was calculated for the i.v. dose as the ratio of compound recovered in the urine to the corresponding AUC. CL_R was not calculated for the oral dose, since renal excretion had not yet plateaued at the end of the urine collection interval.