TABLE 2

Physiologic and compound-specific fixed model parameters associated with the disposition of AKP-001 and metabolites in rats

Parameters	Unit	Values	Sources
Physiologic
V_h	l/kg	0.078	Davies and Morris, 1993
Q_h	l/kg	3.3	Davies and Morris, 1993
V_lumen	l/kg	0.028^a	McConnell et al., 2008
AKP-001
K_p,AKP		1^b
F_AKP		0.01^c
M1
K_p,M1		1^b
CL_r,M1	l/h/kg	0.415^d
FaFg_M1		1^b
M2
K_p,M2		1^b
FaFg_M2	H	0.923^e
Lag time		1.5^f

↵^a The sum of small intestine and large intestine water content reported by McConnell et al., 2008.
↵^b Liver-plasma concentration partition coefficients of AKP-001 and metabolites, and intestinal availability of M1 were assumed to be one.
↵^c F_AKP was calculated by dividing the dose-normalized AUC of AKP-001 after oral dosing to that after intravenous dosing.
↵^d CL_r,M1 was estimated by dividing the total amount of M1 excreted in urine by the AUC of M1 after oral administration of AKP-001.
↵^e Intestinal availability of M2 was calculated by dividing the hepatic availability by the oral bioavailability (see Materials and Methods).
↵^f Lag time for the formation of M2 in gut was considered on the basis of plasma M2 concentration-time profiles after oral administration of AKP-001.