Relationship of quantitative structure and pharmacokinetics in fluoroquinolone antibacterials

Table 1 Pharmacokinetic data of fluoroquinolones from human studies

Compounds		PK parameters						References
		1AUC0-∞ (μg·h/mL)		1t1/2(h)		1Cmax (mg/L)
No.	Name	Range	Average	Range	Average	Range	Average
Training set
1	Amifloxacin	5.5-5.62	5.57	3.58-4.83	4.14	0.9-1.26	1.14	9, 10
2	Balofloxacin	8.55	8.55	7.8	7.8	1.08	1.08	11
3	Ciprofloxacin	2.12-3.53	2.56	3.01-4.7	4.16	0.4-0.69	0.56	12-15
4	Clinafloxacin	4.63-5.93	5.34	5.09-6.13	5.74	0.6-0.84	0.72	16-18
5	DW116	18.54-23.3	21.86	14.53-18.7	15.82	1.1-1.22	1.17	19
6	Enoxacin	2.9-5.47	4.36	2.35-4.98	3.54	0.62-0.81	0.66	20-22
7	Gatifloxacin	6.5-8.92	7.87	6.52-8.6	7.46	0.84-1.03	0.9	23-26
8	Gemifloxacin	2.79-3.43	3.02	5.87-8.2	6.65	0.46-0.73	0.56	27-29
9	Grepafloxacin	2.83-4.05	3.43	9.2-12.7	11.53	0.24-0.41	0.32	11, 12, 30, 31
10	Levofloxacin	8.96-9.5	9.33	6-7.4	6.78	0.16-0.3	0.24	32-34
11	Lomefloxacin	8.05-13.53	9.84	5.5-12.7	7.73	0.95-1.18	1.06	35-37
12	Norfloxacin	1.7-1.85	1.77	3.5-4.02	3.7	0.32-0.36	0.33	38-40
13	Ofloxacin	6.68-11.64	7.67	4.6-6.7	5.32	0.71-1.33	0.87	41-45
14	Pefloxacin	24.4-40.78	29.97	10.9-15.06	14.63	1.03-1.68	1.44	46-48
15	Rufloxacin	35.8-44.03	39.43	28.2-40	34.25	0.68-1.13	0.99	49-52
16	Sitafloxacin	5.62-6.02	5.88	4.6-7	5.4	0.9-0.93	0.92	53-54
17	Sparfloxacin	8.08-11.96	8.35	16.5-25.56	20.06	0.23-0.4	0.34	55-57
18	Temafloxacin	7.42-10.63	8.45	7.8-10.6	8.55	0.61-0.9	0.74	58-60
19	Trovafloxacin	9.75-14.47	11.91	7.8-10.8	9.66	0.97-1.5	1.23	61-63
Test set
20	Difloxacin	26.6-28.3	27.8	20.6-28.8	25.7	1.02-1.1	1.04	64
21	Fleroxacin	16.3-20.65	18.13	7.9-13	11.02	1.19-1.58	1.4	32, 65, 66
22	Tosufloxacin	1.49-3.3	2.62	3.6-4.85	4.02	0.21-0.4	0.34	67-69

¹AUC_0-∞ is area under the plasma concentration-time curve from time zero to infinity; t_1/2 is elimination half life; Cmax is maximum concentration of the drug in plasma.

Table 2 Descriptors used in this paper

Descriptors	Physicochemical meaning
SA7	Surface area (grid) of R7
V7	Volume of R7
HE7	Hydration energy of R7
LP7	Logp of R7
RF7	Refractivity of R7
P7	Polarizability of R7
MW7	Molecular weight of R7
SA1	Surface area (grid) of R1
V1	Volume of R1
HE1	Hydration energy of R1
LP1	Logp of R1
RF1	Refractivity of R1
P1	Polarizability of R1
MW1	Molecular weight of R1

Table 3 Descriptors for group R7 of all fluoroquinolones compounds

No.	R7
	SA7	V7	HE7	LP7	RF7	P7	MW7
1	271.21	398.4	5.48	-0.36	27.44	11.56	99.16
2	299.04	445.86	5.04	-0.15	31.33	13.39	113.18
3	247.54	347.95	1.46	-0.72	22.15	9.72	85.13
4	248.59	344.96	0.9	-1	21.91	9.72	85.13
5	266.41	382.26	5.33	-0.36	27.44	11.56	99.16
6	251.07	350.09	1.58	-0.72	22.15	9.72	85.13
7	265.94	383.08	3.5	-0.31	26.57	11.56	99.16
8	300	442.55	-2.21	-0.28	35.48	14.96	142.18
9	261.99	381	3.58	-0.31	26.57	11.56	99.16
10	264.36	391.96	5.45	-0.36	27.44	11.56	99.16
11	260.22	378.35	3.68	-0.31	26.57	11.56	99.16
12	250.06	350.92	1.37	-0.72	22.15	9.72	85.13
13	269.89	397.69	5.39	-0.36	27.44	11.56	99.16
14	258.05	374.48	5.68	-0.36	27.44	11.56	99.16
15	258.5	378.79	5.73	-0.36	27.44	11.56	99.16
16	281.66	422.58	3	-0.4	28.87	12.62	111.17
17	298.38	442.76	5.55	0.11	30.99	13.39	113.18
18	266.8	385.12	3.43	-0.31	26.57	11.56	99.16
19	244.47	346.87	4.31	-1.24	24.6	10.78	97.14
20	260.91	378.28	5.31	-0.36	27.44	11.56	99.16
21	264	387.29	5.61	-0.36	27.44	11.56	99.16
22	231.53	320.13	2.75	-1	21.91	9.72	85.13

Table 4 Descriptors for group R1 of all fluoroquinolones compounds

No.	R1
	SA1	V1	HE1	LP1	RF1	P1	MW1
1	162.65	191.65	-4.39	-0.41	6.5	3.64	30.05
2	184.12	230.99	2.6	1.13	10.1	5.41	41.07
3	183.13	229.07	2.59	1.13	10.1	5.41	41.07
4	181.83	225.71	2.61	1.13	10.1	5.41	41.07
5	232.61	320.17	-3.57	1.43	24.71	9.18	96.08
6	171.57	206.82	0.73	1.32	7.29	4.35	29.06
7	192.14	241.82	2.56	1.13	10.1	5.41	41.07
8	180.91	225.56	2.61	1.13	10.1	5.41	41.07
9	185.87	233.6	2.57	1.13	10.1	5.41	41.07
10	209.76	274.58	0.58	2.4	13.05	6.37	58.08
11	173.79	211.56	0.71	1.32	7.29	4.35	29.06
12	172.99	213.28	0.7	1.32	7.29	4.35	29.06
13	213.93	278.93	0.71	2.4	13.05	6.37	58.08
14	172.31	210.04	0.72	1.32	7.29	4.35	29.06
15	187.74	241.74	-1.24	0.8	15.93	7.69	60.11
16	194.84	249.45	2.6	0.82	9.92	5.32	59.06
17	193.09	243.16	2.55	1.13	10.1	5.41	41.07
18	246.11	343.09	-3.4	2.14	26.43	9.8	113.09
19	246.34	343.09	-3.4	2.14	26.43	9.8	113.09
20	239.88	334.78	-2.47	2	26.21	9.89	95.1
21	168.2	205.76	0.8	0.92	7.37	4.26	47.05
22	248.12	343.14	-3.4	2.14	26.43	9.8	113.09

Table 5 QSPkR models from the training set data

No.	Model	R2	R	F	S	LOF
AUC	ln(AUC) = 2.27895 + 1.22614 (HE7) + 9.96141 (P7) - 20.5953 (V7) + 9.13637 (SA7)	0.737	0.858	9.801	0.550	0.472
t1/2	ln(t1/2) = 1.49842 + 1.80503 (P7) + 0.492241 (HE7) - 5.26324 (V1) + 3.53476 (P1)	0.729	0.854	9.400	0.555	0.280
Cmax	ln(Cmax) = 2.96161 - 5.92537 (V1) + 2.15698 (MW1) + 0.206369 (P7) + 0.26873 (HE7)	0.327	0.572	1.697	-0.093	0.523

Table 6 Predicted and observed data of the compounds in the test set

Compounds	Observed		Predicted
	AUC	t1/2	AUC	t1/2
20	27.8	25.7	17.431	16.395
21	18.13	11.02	13.269	9.388
22	2.62	4.02	12.034	6.852