| OBJECTIVESTo study the absorption mechanism, pharmacokinetics, absolute bioavailability, tissue distribution characters, plasma protein binding rate, and liver extraction of AKF-PD in SD rats.METHODS1. Absorption mechanism study of AKF-PD.The absorption kinetics and absorption sites were investigated by using in situ intestine perfusion method in SD rats. The AKF-PD concentration in intestine perfusate was detected by HPLC-UV.2. Pharmacokinetics and absolute bioavailability study of AKF-PD.AKF-PD suspension was orally administrated to rats at dose levels of 62.5, 125, 250, 375, 500, and 1000 mg·kg-1. Plasma concentration was determined by HPLC-UV. The data was fit by DAS 2.0 to calculate the pharmacokinetics parameters. In order to evaluate the absolute bioavailability, AKF-PD was administrated to rats orally or injected by tail vein at the dose level of 32.5 mg·kg-1.3. Tissue distribution study of AKF-PD.At 0.25 h, 1.5 h, 4.0 h and 8.0 h after administration AKF-PD suspension at a single dosage of 250 mg·kg-1, one group of rats were sacrificed at one time. Different organs and tissues including liver, kidney, lung, heart, testes, stomach, brain, spleen, intestine, skeletal muscle, gonads, and fat were collected. After washing with normal saline and weighted, all organs and tissues were prepared to homogenate with normal saline in 3 time volum of tissue or organ weight. The AKF-PD concentration was detected by HPLC-UV.4. Plasma protein binding test of AKF-PD.The plasma protein binding rate of AKF-PD in SD rats and human was determined by dialysis balance method. 5. Liver extraction rate test of AKF-PDThe liver extraction rate of AKF-PD in SD rats was determinated by once-through liver perfusion.RESULTS1. Absorption mechanism study of AKF-PD.The permeability rate of AKF-PD was 0.318±0.065 h-1, 0.350±0.021 h-1, and 0.337±0.030 h-1 after perfused 4 hours respectively at low, middle and high concentration, and there was no significant difference due to perfusate concentration. The permeability of AKF-PD in colon was poorer than that in induodenum, jejunum and ileum.2. Pharmacokinetics and absolute bioavailability study of AKF-PD.The pharmacokinetics parameters of AKF-PD in SD rats after oral administration different dose levels were caculated in two-compartmental model. At the dose of 62.5 mg·kg-1, the main pharmacokinetics parameters of AKF-PD were as follows: Cmax was 8.63±2.42 mg·L-1, tmax was 0.33±0.12 h, AUC（0-t） was 17.90±5.93 mg·L-1·h, t1/2β was 1.47±0.45 h, ClF为3.83±1.72 L·h-1·kg-1; At the dose of 125 mg·kg-1, Cmax was 15.01±7.81 mg·L-1, tmax was 0.35±0.13 h, AUC（0-t） was 25.91±11.39 mg·L-1·h, t1/2β was 1.61±0.60 h, Cl/F was 4.99±1.98 L·h-1·kg-1; At the dose of 250 mg·kg-1, Cmax was 29.83±18.89 mg 222 L-1, tmax was 0.58±0.12 h, AUC（0-t） was 76.30±45.09 mg·L-1·h, t1/2β was 1.94±0.83 h, Cl/F was 4.05±1.87 L·h-1±kg-1; At the dose of 375 mg·kg-1, Cmax was 47.15±20.80 mg·L-1, tmax was 0.73±0.28 h, AUC（0-t） was 116.72±47.41 mg·L-1·h, t1/2β was 1.87±0.92 h, Cl/F was 4.03±1.40 L·h-1·kg-1; At the dose of 500 mg·kg-1, Cmax was 78.87±49.09 mg·L-1, tmax was 0.81±0.49 h; AUC（0-t） was 221.15±210.30 mg·L-1·h, t1/2β was 3.25±1.48 h, Cl/F was 4.12±2.40 L·h-1·kg-1.In the multiple dose study, the main pharmacokinetics parameters of AKF-PD were as follows: Cmax was 5.48±2.85 mg·L-1, tmax was 0.48±0.14 h, AUC（0-t） was 10.44±6.33 mg·L-1·h,t1/2β was 1.10±0.40 h, Cl/F was 27.94±14.11 L·h-1·kg-1.In the absolute bioavailability study, the pharmacokinetics parameters of AKF-PD after vein injection were as follows: AUC（0-t） was 42.65±16.12 mg·L-1·h, t1/2β was 1.74±1.19 h, Cl was 0.78±0.49 L·h-1·kg-1; the pharmacokinetics parameters of AKF-PD after oral administration were as follows: Cmax was 6.10±1.16 mg·L-1, tmax was 0.58±0.26 h, AUC（0-t） was 11.58±6.90 mg·L-1·h, t1/2β was 1.70±1.26 h, Cl/F was 3.47±1.52 L·h-1·kg-1. The absolute bioavailability was 27.2 %.3. Tissue distribution study of AKF-PD.The maximum concentration of AKF-PD occurred in tissues and plasma at the same time （about 15 min）. The distribution of AKF-PD in SD rats has no significant difference between those tissues or organs in concentration.4. Plasma protein bingding test of AKF-PD.The plasma protein binding of AKF-PD had been balanced after 12 hours. At the three concentration levels, the SD rats plasma protein binding rate of AKF-PD was 33.22±3.14%, 38.74±3.22%, and 47.80±3.15 %; the human plasma protein binding rate of AKF-PD was 36.97±10.56 %, 32.95±3.16 %, and 42.11±3.98 %.5. Liver extraction rate test of AKF-PD.The liver extraction rate of AKF-PD in SD rats was 23.84±9.52 %.CONCLUSIONS1. In the range from 0.25 mg·mL-1 to 1.00 mg·mL-1 of the perfusate concentration, the absorption of AKF-PD conformed to the first-order kinetics; The AKF-PD could be absorbed in the all intestine segments, and the absorption capacity of colon was poorer than that of duodenum, jejunum and ileum.2. In the dose range from 62.5 mg·kg-1 to 375 mg·kg-1, the process of AKF-PD in SD rats conformed to first order kinetics. Over this range, t1/2β lengthened with the dose increasing, and the pharmacokinetics of AKF-PD belonged to nonlinear pharmacokinetics.3. The distribution of AKF-PD in SD rats has no tropism.4. The plasma protein binding of AKF-PD was low, and there was no significant difference between rat plasma and human plasma.5. The liver extraction rate of AKF-PD in SD rats was low. |
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