Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents

Abstract

P-glycoprotein (P-gp) inhibition has been studied to overcome multidrug resistance in cancer chemotherapy but failed in clinical trials due to low/toxic effects. Recently, a dual modulation of transporters and natural derivatives have been examined to surmount this limitation. We examined breast cancer resistance protein (BCRP) inhibition in vitro and in vivo by P-gp inhibitors derived from natural compounds in previous studies. P-gp inhibitors increased the accumulation of the anticancer drug, topotecan (TPT)—a substrate of P-gp and BCRP, albeit with higher affinity for BCRP—in BCRP-overexpressing cells, resulting in cell death. These dual inhibitors, when orally co-administered with TPT, enhanced TPT bioavailability with slightly reduced total oral clearance (Clt/F) in rats. In xenograft mice, they strengthened oral TPT-induced tumor reduction with no alterations in body weight. Moreover, we investigated the effects of an oral drug formulation (Cremophor® EL, Tween® 80, and polyethylene glycol 400) on the transporters function. The excipients increased TPT accumulation in P-gp- or BCRP-overexpressing cells. Oral TPT bioavailability was higher with the formulation than with a control, as shown by the increases in the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve from zero to infinity (AUCINF) (p < 0.01). Therefore, oral TPT bioavailability was enhanced by P-gp/BCRP dual inhibition, which resulted in a formulation-mediated increase in absorption and decrease in elimination, and a dual inhibitor-mediated decrease in elimination. These results suggest that the combination of dual inhibition by a natural derivative and the drug formulation can be a useful clinical approach.

Nanomedicine for increasing the oral bioavailability of cancer treatments

“…Many investigations are routinely performed to enhance the absorption of oral formulations. In particular, these studies aim to optimize drug solubility/permeability properties and inhibit P-gp and BCRP transporters [ 136 ] using excipients that can eventually favor drug absorption. For example, D-α-tocopherol polyethylene glycol 1000 succinate and PEG-400 were shown to increase the solubility and absorption of etoposide [ 137 ], and the research on generating novel, safe solvents is very intense [ 138 ].…”

Development and Validation of an HPLC Method for Analysis of Topotecan in Human Cerebrospinal Fluid and Its Application in Elimination Evaluation of Topotecan after Intraventricular Injection

“…Arimori et al [ 17 ] reported that the open/closed state of the ring changed the pharmacokinetics of CPT-11 and its affinity for P-glycoprotein, which is responsible for the extracellular transport of CPT-11. Topotecan is also a substrate for P-glycoprotein and breast cancer-resistance proteins [ 18 , 19 , 20 ]. Among the functional components of the blood–brain barrier and the blood–CSF barrier [ 21 ], proteins of the ATP-binding cassette transporter family appear to play a significant role in transporting topotecan and are likely to affect its distribution in the brain parenchyma and CSF compartments [ 18 , 22 ].…”

Approaches to minimize the effects of P‐glycoprotein in drug transport: A review

“…The USFDA drafted drug interaction guidelines for MDR1 (P‐gp) and BCRP (ABCG2) (Ou et al, 2021; Lee et al, 2021). In the epithelial cells, if the basal to apical (B–A) to apical to basal (A–B) efflux ratio of the new molecular entity (NME) is ≥2, then it is taken into account as a potential substrate of the P‐gp.…”