Table 2

Metabolism of phosphoramidate triesters of d4TMP or AZTMP after overnight incubation with pig liver carboxylesterase, human serum, CEM cell extract, and mouse serum

Number	Amino Acid/Ester	Intact Prodrug and Its Metabolism after Incubation with:^2-a
		Carboxylesterase		Human Serum		CEM Extract		Mouse Serum
		Intact Prodrug	IM	AAM	Intact Prodrug	IM	AAM	Intact Prodrug	IM	AAM	Intact Prodrug	IM	AAM
		%
d4TMP derivatives
1	l-Alanine/Bz	0	0	100	20	0	80	8	0	92	0	0	100
2	l-Alanine/Me	0	0	100	36	0	62^2-b	14	0	84^2-b	0	0	98^2-b
3	l-Alanine/Et	0	0	100	76	0	23^2-b	26	0	72^2-b	0	0	98^2-b
4	Methyl-l-aspartic acid/Me	0	0	100	18	0	82	0	0	99^2-b	0	0	99^2-b
5	d-Alanine/Me	0	0	100	66	0	34	58	0	42	9	0	91
6	Glycine/Me	0	0	100	55	0	45	49	0	51	0	0	100
7	l-Leucine/Me	13	0	87	79	0	21	52	0	48	20	0	80
8	l-Valine/Me	100	0	0	100	0	0	100	0	0	100	0	0
9	l-Methionine/Me	11	0	89	40	0	60	33	0	67	15	0	85
10	l-Phenylalanine/Me	0	0	100	46	0	54	37	0	63	18	0	82
11	Methyl-l-glutamic acid/Me	0	35	65	38	34	28	25	40	35	0	25	75
12	β-Alanine/Et	0	100	0	92	8	0	74	26	0	0	100	0
AZTMP derivatives
13	Glycine/Me	0	0	100	52	0	48	ND	ND	ND	0	0	100
14	l-Alanine/Me	0	0	100	42	0	58	8	0	90^2-b	0	0	98^2-b
15	l-Leucine/Me	0	70	30	53	34	13	24	60	16	7	76	16^2-b
16	d-Alanine/Me	0	0	100	54	0	45^2-b	54	0	45^2-b	0	0	98^2-b
17	l-Phenylalanine/Me	0	0	100	42	40	18	38	43	19	29	31	40
18	Methyl-l-glutamic acid/Me	0	51	49	32	45	23	12	39	49	9	37	54

↵2-a The phosphoramidate derivatives of d4TMP or AZTMP were incubated overnight with carboxylesterase or with biological media, after which the remaining intact prodrug and the IM and AAM following metabolites were determined by HPLC.
↵2-b Due to the minor formation of ddNMP + ddN (≤2%), the total of intact prodrug + IM + AAM was not 100%.
N.D., not determined.