Table 3. In Vitro Stability in Liver Microsomes and Pharmacokinetic Parameters for 8, 9, and 15 in Mice^a.

	stability in liver microsome				oral PK parameters					intravenous PK parameters
compd	% remain at 1 h, mouse + NADPH	% remain at 1 h, mouse – NADPH	% remain at 1 h, human + NADPH	% remain at 1 h, human – NADPH	Cmax (μg/mL)	Tmax (h)	AUC0-inf (h·μg/mL)	T1/2 (h)	F (%)	CL (mL/h/kg)	Vss (mL/kg)	AUC0–inf (h·μg/mL)	T1/2 (h)
8 (an acid)b	nde	nd	nd	nd	19.5	0.25	8.62f	0.23	67	2326	848	4.3	1.1
9 (an ester)c	0	0	0	0	0.16	0.25	0.10	1.0	23	12463	926	0.4	0.3
8 from 9d					0.92	0.25	0.61	1.5	29			0.99	0.13
15 (an amide)c	97	100	87	100	1.38	0.25	2.29	2.1	99	2261	973	2.2	0.4

^aAbbreviations: C_max, maximum concentration of drug in plasma; T_max, time to maximum concentration of drug in plasma; AUC_0–inf, area under the curve extrapolated to infinity; T_1/2 terminal half-life; F, oral bioavailability; CL, clearance; V_ss, volume of distribution at steady state.

^bOral dosing at 30 mg/kg and intravenous dosing at 10 mg/kg.

^cOral dosing at 5 mg/kg and intravenous dosing at 5 mg/kg.

^dThe acid 8 detected from studies of the ester 9 because there was conversion of 9 to 8 in vivo.

^eNot determined.

^fThis is AUC_0–2h.