TABLE 2

Kinetic parameters from different in vitro assays used to characterize propofol CL_int,P450 and CL_int,UGT in the presence and absence of 2% BSA and used in a whole-body PBPK model to predict propofol in vivo clearance and blood concentration-time profiles

Data are the mean (± S.D.) of n = 3 experiments, each performed in duplicate, with the exception of CL_int,UGT in HIM substrate depletion assays where n = 1.

Assay Type	Parameter	Without BSA				With 2% BSA
Assay Type	Parameter	HLMs	HKMs	HIMs	Hepatocytes	HLMs	HKMs	HIMs
Metabolite formation	V_max (pmol/min per milligram protein)	1460 (244)	5220 (726)	1280 (147)	NT	1390 (101)	4310 (1406)	1470 (457)
	K_m (µM)	107 (39.9)	91.0 (12.8)	458 (65.4)	NT	5.22 (0.360)	3.45 (0.931)	133 (55.6)
	CL_int,UGT (ml/min per gram tissue)^{^a}	0.594 (0.215)	0.735 (0.0247)	0.0581 (0.00652)	NT	10.6 (0.936)	17.0 (7.62)	0.237 (0.0551)
Substrate depletion	CL_int,UGT (ml/min per gram tissue)^{^a},^{^b}	2.71 (0.18)	1.17 (0.41)	1.29 (—)	7.63 (1.68)^{^c}	8.05 (0.46)	13.1 (1.66)	2.13 (—)
	CL_int,P450 (ml/min per gram tissue)^{^a}	9.12 (2.03)	ND	ND	10.2^{^d}	18.1 (0.455)	ND	ND
	CL_{int,P450 & UGT} (ml/min per gram tissue)^{^a}	NT	NT	NT	17.9 (3.36)^{^c}	NT	NT	NT

BSA, bovine serum albumin; HIM, human intestinal microsomes; HKM, human kidney microsomes; HLM, human liver microsomes; (—), not applicable; ND, no depletion observed; NT, not tested; PBPK, physiologically based pharmacokinetic.
↵^a In vitro CL_int data scaled with microsomal recovery factors (40, 12.8, and 20.6 mg protein/g tissue for HLMs, HKMs, and HIMs, respectively) or hepatocellularity (120 × 10⁶ cells/g tissue) to give scaled CL_int/g tissue.
↵^b Data presented previously in Gill et al. (2012).
↵^c In-house data, where CL_int,P450 and CL_int,UGT were determined in hepatocytes in the absence of ABT and CL_int,UGT was determined in hepatocytes in the presence of ABT.
↵^d Hepatocyte CL_int in absence of ABT – hepatocyte CL_int in presence of ABT.