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Abstract
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 AUCinf of PTX without alterations in the Cmax value. The elimination half-life was extended and the oral clearance decreased. Additionally, the Tmax 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.
Highlights
Paclitaxel (PTX) is a widely-used anticancer drug that is known to have poor bioavailability due to its low solubility and membrane permeability [1]
Because the efflux transporter is the primary cause of multi-drug resistance (MDR) and alters the pharmacokinetics of various drugs, P-gp modulation could counter the MDR and increase the BA of orally delivered drugs
We demonstrated that compound 4, piperazine iminodiacetic acid triamide, which was selected a potential P-gp inhibitor from several piperazine derivative candidates in vitro (Figure 1), increased as a potential P-gp inhibitor from several piperazine derivative candidates in vitro (Figure 1), the BA of PTX, known to have poor BA, as well as a P-gp substrate anticancer drug [1]
Summary
Paclitaxel (PTX) is a widely-used anticancer drug that is known to have poor bioavailability (below 10%) due to its low solubility and membrane permeability [1]. A five-hydroxychromone linked linked piperazine unit was identified as a highly active P-gp-mediated MDR modulator [17]. 1.5–2-fold greater effect on antiproliferative activity than the DHA compounds without piperazine greater effect on antiproliferative activity than the DHA compounds without piperazine substitution substitution [18]. We demonstrated that compound 4, piperazine iminodiacetic acid triamide, which was selected a potential P-gp inhibitor from several piperazine derivative candidates in vitro (Figure 1), increased as a potential P-gp inhibitor from several piperazine derivative candidates in vitro (Figure 1), the BA of PTX, known to have poor BA (below 10%), as well as a P-gp substrate anticancer drug [1]. Increased the BA of PTX, known to have poor BA (below 10%), as well as a P-gp substrate anticancer with a draggy absorption and a slow elimination in rats.
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