TABLE 6

In vitro metabolism and in vivo pharmacokinetic parameters of tamoxifen, C4, or C5 by MLM/human liver microsomal incubation and by subcutaneous/oral administration in female C57BL/6J mice, respectively

Data represent the mean ± S.D. percentage of drug conjugate remaining from microsomal incubations (n = 3) unless indicated otherwise.

Drug	Route	In Vitro Metabolism in Microsomes				In Vivo Metabolism in Female C57BL/6J Mice
Drug	Route	0 min	5 min	10 min	20 min	T_max	C_max	Half-Life	AUC_0–24	Relative Bioavailability
		%				h	ng/ml	h	h × ng/ml	%
Tamoxifen
MLM	s.c.	100.67 ± 9.44	74.79 ± 10.13	60.36 ± 11.59		6	27.5	4.6	259.4
HLM		97.16 ± 7.84		80.03 ± 3.79	58.35 ± 24.55
C4
MLM	s.c.	107.81 ± 16.14	88.36 ± 11.92	65.55 ± 14.60		6	40.9	6.8	289.1
HLM	p.o.	95.20 ± 20.19		79.22 ± 8.43	65.78 ± 8.76	0.5	102.6	3.6	143.7	4.52
C5
MLM	s.c.	112.11 ± 16.02	85.39 ± 12.22	69.45 ± 14.23		6	31.0	5.3	229.1
HLM	p.o.	95.82 ± 10.62		75.32 ± 5.47	61.72 ± 4.96	24	8.9	6.9	1.6	0.11

Tamoxifen, C4, or C5 drug conjugates (10 μM) were incubated with MLMs or HLMs over time (10 minutes for MLMs and 20 minutes for HLMs) and the amount remaining at each timepoint was measured by HPLC-UV detection. Data were analyzed by one-way ANOVA followed by the Newman–Keuls post hoc t test where significance was defined as P < 0.05. Mice were administered a 1 mg/kg dose by the subcutaneous route or a 10 mg/kg dose by the oral route (conjugates only). HLM, human liver microsome.