TABLE 1

Incubation medium and hepatocyte concentrations of atorvastatin, pitavastatin, AZ3, and AZ25 after incubation of the four compounds with isolated rat and human hepatocytes The concentrations of the four P450 inhibitors in the incubation medium (determined by rapidly centrifuging down the hepatocytes and sampling the supernatant) at time 0 and 10 min are defined as T₀ and T₁₀, respectively. T₁₀^hep is defined as the intracellular concentration at 10 min (determined by rapidly centrifuging the hepatocytes through an oil layer to separate the cells from the incubation medium for analysis; see Materials and Methods). % Drop refers to the drop in media concentrations (from T₀ to T₁₀) of the four compounds. All values are means of three replicate experiments.

Uptake substrate	Start Conc.	T₀	Rat					Human
Uptake substrate	Start Conc.	T₀				T₁₀	T₁₀^hep	% drop	T₀	T₁₀	% drop
	μM			μM				μM
Atorvastatin	50	44	23	6654	48	46	40	13
	17	16	8	2176	48	16	13	19
	6	4.2	1.1	980	75	4.4	3.19	27
	2	1.8	0.4	390	74	1.8	1.13	37
	0.6	0.5	0.1	119	75	0.5	0.32	35
	0.2	0.2	0.04	39	76	0.2	0.12	35
Pitavastatin	50	40	23	6846	44	47	43	8
	17	15	8	2360	51	15	15	6
	6	4.3	1	1001	78	4.7	3.7	21
	2	1.8	0.3	420	82	1.6	1.3	19
	0.6	0.5	0.1	121	78	0.5	0.45	14
	0.2	0.2	0.04	41	80	0.2	0.13	23
AZ3	50	43	22	6396	45	47	34	27
	17	14	5	2933	62	15	11	30
	6	4	1.2	905	67	5	3.00	34
	2	1.7	0.6	347	64	1.9	1.10	43
	0.6	0.5	0.2	111	69	0.5	0.29	47
	0.2	0.2	0.04	40	77	0.2	0.09	50
AZ25	50	44	28	5000	34	45	36	20
	17	15	7	2323	49	15	10	30
	6	4.3	1.8	746	54	4.2	2.6	39
	2	1.8	0.8	304	57	1.8	1.1	40
	0.6	0.5	0.2	103	64	0.6	0.3	52
	0.2	0.2	0.05	36	71	0.2	0.1	47