Effects of Piperazine Derivative on Paclitaxel Pharmacokinetics
- 주제(키워드) piperazine derivatives , P-glycoprotein inhibitor , pharmacokinetics , bioavailability , paclitaxel
- 주제(기타) Pharmacology & Pharmacy
- 설명문(일반) [Lee, Jaeok; Chae, Song Wha; Oh, A. Reum; Yoo, Ji Hye; Choo, Hea-Young Park; Rhie, Sandy Jeong; Lee, Hwa Jeong] Ewha Womans Univ, Coll Pharm, Seoul 03760, South Korea; [Lee, Jaeok; Chae, Song Wha; Oh, A. Reum; Yoo, Ji Hye; Choo, Hea-Young Park; Lee, Hwa Jeong] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Rhie, Sandy Jeong] Ewha Womans Univ, Div Life & Pharmaceut Sci, Seoul 03760, South Korea
- 등재 SCIE, SCOPUS
- OA유형 gold, Green Published, Green Submitted
- 발행기관 MDPI
- 발행년도 2019
- URI http://www.dcollection.net/handler/ewha/000000160268
- 본문언어 영어
- Published As http://dx.doi.org/10.3390/pharmaceutics11010023
- PubMed https://pubmed.ncbi.nlm.nih.gov/30626065
초록/요약
Paclitaxel (PTX) is an anticancer agent that is used to treat many cancers but it has a very low oral bioavailability due, at least in part, to the drug efflux transporter, P-glycoprotein (P-gp). Therefore, this study was performed to enhance oral bioavailability of PTX. In this study, we investigated the effects of several piperazine derivatives on P-gp function in vitro. Compound 4 was selected as the most potent P-gp inhibitor from the in vitro results for examining the pharmacokinetic (PK) changes of PTX in rats. Compound 4 increased the AUC(inf) of PTX without alterations in the C(max )value. The elimination half-life was extended and the oral clearance decreased. Additionally, the T-max was delayed or widened in the treatment groups. Therefore, the bioavailability (BA) of PTX was improved 2.1-fold following the co-administration of 5 mg/kg of the derivative. A piperazine derivative, compound 4, which was confirmed as a substantial P-gp inhibitor in vitro increased the BA of PTX up to 2-fold by a lingering absorption, in part due to inhibition of intestinal P-gp and a low oral clearance of PTX. These results suggest that co-administering compound 4 may change the PK profile of PTX by inhibiting P-gp activity in the body.
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