In vivo and in vitro evidence of the sex-dependent pharmacokinetics and disposition of G004, a potential hypoglycemic agent, in rats

Linlin Hu a, b, c, Xiaobing Li a, c, Li Ding a, c, *, Janvier Engelbert Agbokponto a, c, Bing Liu a, c, Shuisheng Zhonga, Xiaoyu Zhanga, Yiwei Dua

aDepartment of Pharmaceutical Analysis, ChinaPharmaceuticalUniversity, 24 Tongjiaxiang, Nanjing 210009, China

bDepartment of Pharmaceutical Sciences, ZhejiangUniversity of Technology, Hangzhou 310014, PR China

c Key laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, 24 Tongjiaxiang, Nanjing 210009, China

The supplemental Tables:

Table 1 The concentrationof G004 in selected tissues for male and female rats at 10 min, 20 min, 2 h, 8 h and 36 h afterdose

Tissue/Organ / Concentration (ng/g) at time after dose administration
10 min / 20 min / 2 h / 8 h
Male / Female / Male / Female / Male / Female / Male / Female
Brain / ND / ND / ND / ND / ND / ND / ND / ND
Muscle / 7.361 ± 3.1 / 6.355 ± 0.8 / 2.027 ± 1.0 / 13.81 ± 2.9 / ND / 20.99 ± 3.6 / ND / 19.76 ± 1.8
Fat / 5.768 ± 1.2 / 7.868 ± 2.4 / 10.58 ± 3.3 / 19.43 ± 3.8 / 2.135 ± 0.6 / 27.53 ± 4.0 / 7.160 ± 5.8 / 17.97 ± 4.0
Testis/Ovary / 24.293 ± 0.6 / 70.4 ± 7.1 / 17.99 ± 0.8 / 22.04 ± 6.1 / 5.206 ± 0.5 / 45.84 ± 30.6 / 5.810 ± 0.1 / 6.797 ± 1.7
Kidney / 254.5 ± 88.4 / 472.3 ± 58.4 / 278.9 ± 50.7 / 358.7 ± 275.8 / 111.6 ± 31.0 / 673.5 ± 259.0 / 38.30 ± 0.6 / 85.44 ± 29.3
Heart / 66.24 ± 37.6 / 84.92 ± 25.6 / 836.8 ± 389.2 / 1076 ± 827.4 / 26.63 ± 15.1 / 141.23 ± 21.2 / 8.770 ± 5.2 / 10.27 ± 4.7
Spleen / 47.31 ± 29.2 / 17.26 ± 3.3 / 20.15 ± 6.7 / 79.04 ± 5.5 / 7.900 ± 6.1 / 20.68 ± 6.6 / 3.350 ± 0.6 / 12.66 ± 9.4
Lung / 31.51 ± 6.3 / 51.25 ± 17.7 / 39.84 ± 22.6 / 170.4 ± 17.1 / 27.89 ± 17.0 / 317.13 ± 12.4 / 10.11 ± 0.0 / 15.25 ± 6.0
Pancreas / 47.62 ± 42.1 / 27.82 ± 15.9 / 15.72 ± 5.5 / 57.34 ± 0.4 / 7.190 ± 0.4 / 72.51 ± 14.9 / 2.340 ± 0.0 / 22.93 ± 4.7
Liver / 2955 ± 59 / 10089 ± 1146 / 2429 ± 972.5 / 8663 ± 2605 / 894.0 ± 179.3 / 13367 ± 101.7 / 264.8 ± 85.9 / 8207 ± 1910
Stomach / 56586 ± 28599 / 48781 ± 29703 / 18197 ± 443.1 / 41107 ± 8197.6 / 1965 ± 1325 / 62280 ± 17263 / 1119 ± 735.1 / 1559 ± 1319
Large Intestine / 233.8 ± 7.8 / 165.9 ± 63.5 / 876.5 ± 6.0 / 1183 ± 42.4 / 89.10 ± 0.6 / 3079.1 ± 21.3 / 10.30 ± 0.7 / 179.0 ± 2.4
Small Intestine / 1317 ± 11.3 / 5158 ± 156.4 / 2072 ± 23.2 / 4691 ± 17.6 / 950.0 ± 24.2 / 8483 ± 157.7 / 39.00 ± 8.2 / 22.44 ± 3.6
Plasma / 1888 ± 1000 / 738.0 ± 114.8 / 2179 ± 425.4 / 1773 ± 86.30 / 719.0 ± 189.4 / 4110 ± 384.9 / 51.12 ± 17.61 / 841.0 ± 209.3

Note: The concentrationsof G004 in selected tissues for male and female rats at 36 h afterdose were all lower than the LLOQ.

Table 2Cumulation amount of bile, urine and feces excretion of G004 in rats after dose(n=6)

Time(h) / Bile(%) / Time(h) / Urine(%) / Fececs(%)
Male / Female / Male / Female / Male / Female
0-2 / 0.011 ± 0.0039 / 0.023 ± 0.017 / 0-3 / 0.031 ± 0.0050 / 0.023 ± 0.004 / 0.0065 ± 0.0112 / 0.07420 ± 0.1285
4 / 0.022 ± 0.014 / 0.065 ± 0.045 / 8 / 0.054 ± 0.023 / 0.082 ± 0.008 / 17.55 ± 21.00 / 1.433 ± 1.135
6 / 0.030 ± 0.018 / 0.091 ± 0.058 / 11 / 0.060± 0.028 / 0.10 ± 0.009 / 78.82 ± 3.836 / 75.33 ± 12.21
8 / 0.036 ± 0.022 / 0.11 ± 0.068 / 15 / 0.064 ± 0.032 / 0.12 ± 0.012 / 82.86 ± 3.471 / 80.21 ± 8.197
12 / 0.042 ± 0.027 / 0.13 ± 0.072 / 24 / 0.067 ± 0.032 / 0.12 ± 0.012 / 83.97 ± 2.726 / 84.84 ± 4.601
24 / 0.044 ± 0.028 / 0.16 ± 0.074 / 48 / 0.069 ± 0.032 / 0.12 ± 0.012 / 84.61 ± 2.249 / 87.14 ± 3.461
36 / 0.044 ± 0.029 / 0.17 ± 0.080 / 72 / 0.069 ± 0.032 / 0.12 ± 0.012 / 84.61 ± 2.249 / 88.18 ± 2.950

Legends of supplemental Figures:

Fig.S11H NMR Spectrum of the chemical synthesized M3.

Fig.S21H NMR Spectrum of the chemical synthesized M4-2.

Fig.S3TIC chromatograms ofblank rat bile (A) and a bile sample during 0 to 36 h after an intragastric dose of 30 mg/kg G004 in rats (B).