Effect of the ET B Receptor Agonist,IRL-1620,on Paclitaxel Plasma Pharmacokinetics of Breast Tumor Rats

Abstract

Endothelin (ET)-B receptors are expressed in human breast carcinoma. We previously demonstrated that intravenous administration of the ET_B receptor agonist, IRL-1620, to tumor-bearing rats, increased blood perfusion and enhanced delivery of paclitaxel to breast tumor tissue. The present study was conducted to determine whether IRL-1620 alters the pharmacokinetics of paclitaxel. Breast tumor–bearing rats were given 0.3 ml/kg saline or 3 nmol/kg IRL-1620 by intravenous (iv) administration. Fifteen minutes after saline or IRL-1620, 40 μCi/rat ³H-Paclitaxel was administered iv and serial plasma samples were collected until 24 hrs. ³H-Paclitaxel radioactivity in the plasma samples was measured by liquid scintillation counting. Data were fit to a three-compartment model and pharmacokinetic parameters were generated using WinNonlin software. IRL-1620 did not produce any change in the plasma paclitaxel pharmacokinetics of tumor-bearing rats. The AUC_0–∞ (9.43 ± 3.18 μg-hr/ml), clearance (0.69 ± 0.17 l/hr/kg), volume of distribution (10.31 ± 4.54 l/kg), and half-life (1.0 ± 0.32 hrs) of paclitaxel were similar between rats treated with saline or IRL-1620. In conclusion, the ET_B receptor agonist, IRL-1620, does not alter paclitaxel plasma pharmacokinetics and, therefore, could be used to augment the delivery of paclitaxel to the tumor tissue.