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KMID : 0861120150190010145
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Korean Journal of Oriental Preventive Medicine
2015 Volume.19 No. 1 p.145 ~ p.159
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Effect of Gongjindan-gamibang on the Pharmacokinetics Profiles of Sorafenib in Male SD Rats (2) - Single Oral Combination Treatment of Sorafenib 50mg/kg with Gongjindan-gamibang 100 mg/kg, 3.5hr-intervals with 7-day Repeated Treatment -
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Lee Chang-Hyeong
Kim Seung-Mo
Kang Su-Jin
Park Soo-Jin
Song Chang-Hyun
Han Chang-Hyun
Lee Young-Joon
Ku Sae-Kwang
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Abstract
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Objective : In the previous study, co-administration of Gongjindan-gamibang (GJD) with sorafenib increased oral bioavailability of sorafenib through augment the absorption, therefore, the effects of GJD co-administration on the pharmacokinetics of sorafenib were observed after single and 7-day repeated oral co-administration with 3.5 hr-intervals in the present study.
Method : After 50 mg/kg of sorafenib treatment, GJD 100 mg/kg was administered with 3.5 hr-intervals. The plasma were collected at 30 min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of first and last 7th sorafenib treatment, and plasma concentrations of sorafenib were analyzed using LC-MS/MS methods. PK parameters of sorafenib (Tmax, Cmax, AUC, t1/2 and MRTinf) were analysis as compared with sorafenib single administered rats.
Results : GJD markedly inhibited the absorption of sorafenib, from 1 hr to 24 hrs after end of first 3.5 hr-interval co-administration, the Cmax (-43.27%), AUC0-t (-56.29%) and AUC0-inf (-66.70%) of sorafenib in co-administered rats were dramatically decreased as compared with sorafenib single treated rats. However, GJD significantly increased the absorption of sorafenib, from 4 hr to 8 hrs after end of last 7th 3.5 hrinterval co-administration, the AUC0-t (34.08%) and AUC0-inf (37.31%) of sorafenib in co-administered rats were dramatically increased as compared with sorafenib single treated rats.
Conclusion : Although GJD decreased the oral bioavailability of sorafenib through inhibition of gastrointestinal absorptions after end of first 3.5 hr-interval co-administration, it is observed that GJD increases the oral bioavailability of sorafenib as facilitated the absorption after end of last 7th repeated co-administration. Hence, the co-administration of GJD and sorafenib should be avoided in the combination therapy of sorafenib with GJD on anticancer therapy.
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KEYWORD
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Gongjindan-gamibang, Pharmacokinetics, Drug-drug interactions, Rat, Sorafenib, Repeat oral dose
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