Effects of verapamil on etoposide pharmacokinetics after intravenous and oral administration in rats

Abstract

Etoposide is mainly metabolized by cytochrome P450 (CYP) 3A and is a substrate for P-glycoprotein (P-gp). This study examined the effects of verapamil, a CYP3A and P-gp inhibitor, on the pharmacokinetics of etoposide in rats. A single dose of etoposide was administered via oral (p.o.; 10 mg/kg) or intravenous (i.v.; 3.3 mg/kg) routes to rats alone (control animals) or together in combination with verapamil (2 or 6 mg/kg; experimental animals). The presence of verapamil significantly increased the area under the plasma concentration-time curve (AUC); (P < 0.05; 39.2-47.6%) and significantly reduced (P < 0.01; 27.8-31.2%) the total body clearance (CLt) of p.o. administered etoposide. The absolute bioavailability (F) of etoposide increased by 1.38- to 1.47-fold. The presence of verapamil significantly increased (P < 0.01; 38.3-38.9%) the AUC and significantly reduced (P < 0.01; approximately 27%) the total body clearance (CLt) of i.v. administered etoposide. This increased bioavailability suggests that verapamil inhibits metabolic activity and elimination etoposide. The increased bioavailability of etoposide in the presence of verapamil should be taken into consideration for dosage regimens due to a potential drug interaction (DI).

Oral treatment with etoposide in small cell lung cancer – dilemmas and solutions

“…A possible explanation to enhanced bioavailability of oral etoposide by these three aforementioned drugs could be due to an inhibition of CYP450-catalyzed metabolism and ABCB1-mediated efflux in the intestine and/or liver 75–77. Similar results were obtained with verapamil and PSC833 (valspodar), a CYP3A and ABCB1 inhibitor 40,78,79…”

Simultaneous determination of etoposide and a piperine analogue (PA-1) by UPLC–qTOF-MS: Evidence that PA-1 enhances the oral bioavailability of etoposide in mice

“…However etoposide has shortcomings of low and variable bioavailability after oral dosing [9,10]. Currently different pharmacological approaches are being explored in order to demonstrate any potentially useful improvement in rate and extent of etoposide absorption into the systemic circulation in the clinical setting of oral therapy [11][12][13][14][15][16][17].…”

Disposition of everolimus in mdr1a−/1b− mice and after a pre-treatment of lapatinib in Swiss mice

“…Conversely, inhibitors of P-gp may increase the oral absorption of drugs transported by P-gp. For example, verapamil enhanced bioavaibility of etoposide in rats [14]. In vitro study using human intestinal cell line (Caco-2) has shown that everolimus is a potent substrate for P-gp-like mediated efflux and this efflux was completely inhibited by verapamil.…”